07 28 14 Specifications

The eCTD Backbone Files Specification for Module 1
The eCTD BACKBONE FILES SPECIFICATION FOR MODULE 1
Revision History
Date Version Summary of Changes
2003-08-13 1.0 Original version
2004-03-01 1.1 Clarifications to the original version
2006-04-13 1.2 Change to Related Sequence Example
2006-12-13 1.3 Change to XML coding for a supplement to an original application
related sequence example
2012-06-01 2.0 Change to reflect major modifications to Module 1 (admin) and
the use of attributes (Summary of Changes in Appendix 2)
2012-11-01 2.1 Changes include updating the DTD version references and
includes a copy of the updated DTD version 3.1 in Appendix I
(Summary of Changes in Appendix 2)
2013-08-23 2.2 Changes include two additional attributes for m1.15.2.1., updating
the DTD version references and updating the copy of the DTD in
Appendix I (Summary of Changes in Appendix 2)
2014-02-07 2.3 Modified the heading for 1.15.1.5 (Summary of Changes in
Appendix 2)
Version 2.3
TABLE OF CONTENTS
TABLE OF CONTENTS ....................................................................................................................... 1

INTRODUCTION ................................................................................................................................. 1
I. USE OF ATTRIBUTES ................................................................................................................ 1
II. START OF THE MODULE 1 eCTD BACKBONE FILE ........................................................... 2
III. ADMIN ELEMENTS................................................................................................................ 3
A. Applicant-info Element ....................................................................................................... 3
1. ID Element .................................................................................................................... 3
2. Company-name Element .............................................................................................. 3
3. Submission-description Element .................................................................................. 4
4. Applicant-contacts Element .......................................................................................... 4
B. Application-set Element...................................................................................................... 5
1. Application-information Element ................................................................................. 5
2. Submission-information element .................................................................................. 7
3. Building Regulatory Activities ................................................................................... 12
IV. Grouped Submissions .............................................................................................................. 13
V. LEAF ELEMENT........................................................................................................................ 16
VI. SECTION HEADING ELEMENTS FOR MODULE 1 ......................................................... 17
A. M1 Regional Section Headings Requiring Attributes ...................................................... 17
B. M1 Forms .......................................................................................................................... 17
C. Module 1.15 — Promotional Material .............................................................................. 18
APPENDIX 1: M1 Document Type Definition (DTD) Version 3.3 ................................................... 21
APPENDIX 2: Summary of Changes for Versions of The eCTD Backbone Files Specification for
Module 1 .............................................................................................................................................. 42
A. Summary of Changes for Version 2.3............................................................................... 42
B. Summary of Changes for Version 2.2............................................................................... 42
C. Summary of Changes for Version 2.1............................................................................... 42
D. Summary of Changes for Version 2.0............................................................................... 42
List of In-Text tables

Table 1: Attribute List Table.................................................................................................................. 2
Table 2: Submission Types and Descriptions of Use ............................................................................ 9
Table 3: Supplement-Effective-Date-Types and Descriptions of Use ................................................. 10
Table 4: Submission Sub-Types and Descriptions of Use ................................................................... 10
Table 5: Building Regulatory Activities – Scenario 1 ......................................................................... 12
Table 6: Building Regulatory Activities – Scenario 2 ......................................................................... 13
Table 7: Grouped Submissions Limitations and Use ........................................................................... 14
Table 8: Grouped Submission – Scenario 1 ......................................................................................... 15
Table 9: Grouped Submission – Scenario 2 ......................................................................................... 16
Table 10: Form Types and eCTD Location ......................................................................................... 18
Table 11: Promotional Material Audience Types and Descriptions .................................................... 19
Table 12: Promotional Material Doc Types and Descriptions ............................................................. 19
Table 13: Material ID and Issue Date Descriptions ............................................................................. 20
Version 2.3
INTRODUCTION
This document provides specifications for creating the electronic common technical document
(eCTD) backbone file for Module 1 for submission to the FDA. It should be used in conjunction
with the guidance to industry: Providing Regulatory Submissions in Electronic Format — Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.
Font formatting conventions are used in this document to enhance its readability and emphasize
items such as heading elements, attributes, titles, and file names:
• Bold italic font is used for elements and attributes.

• Italic font is used for links, leaf titles, publication titles, file names, and folder names.
The Module 1 eCTD Backbone File (us-regional.xml) includes administrative information and
information for each file submitted in Module 1. The backbone file contains an XML element named
fda-regional:fda-regional, which contains both the admin and m1-regional elements. The
individual file information is provided within an XML element called the leaf element. The leaf
elements are organized using the Module 1 section headings. The Module 1 section headings are
named and organized according to the subject matter of the information contained in the files.
Section headings are provided as XML elements in the m1-regional element of the backbone file.
Administrative information about each submission is provided in the admin element of the backbone
file.
The Module 1 eCTD Backbone File may be used in a wide range of applications and related
submission types; therefore, a specific submission may not use all of the possible section heading
elements. Only include the section headings that reference files in the submission. Empty section
headings should not be included. The admin element should always be included, and it contains two
elements named: applicant-info and application-set. These elements should be included in order as
listed in section III Admin Elements.
The us-regional-v3-3.dtd file (refer to Appendix 1) provides the organization for each element used in
the us-regional.xml file.
I. USE OF ATTRIBUTES
Certain admin and m1-regional heading elements require an attribute to provide information that is
pertinent to the application and submission. The attribute lists are maintained as separate XML files,
and each contains a standard set of codes and display names for each defined attribute type. The
attribute files contain a version number, version date and coded values and display names for each
value. Each coded value has a status of “active” or “inactive” to accommodate future changes; only
coded values with a status of “active” should be submitted. Only the code should be provided as the
attribute value in the appropriate element in the us-regional.xml file. The display name is shown to the
reviewers in the review tool.
The following table contains the names of the attribute type lists and their respective file names.
Refer to the FDA web site for the current versions of each list:
Version 2.3 1
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electronic
Submissions/ucm253101.htm.
Table 1: Attribute List Table

Attribute Type File Name
applicant-contact-type applicant-contact-type.xml
telephone-number-type telephone-number-type.xml
application-type application-type.xml
submission-type submission-type.xml
submission-sub-type submission-sub-type.xml
supplement-effective-date-type supplement-effective-date-type.xml
form-type 1 form-type.xml
promotional-material-audience-type promotional-material-audience-type.xml
promotional-material-doc-type promotional-material-doc-type.xml
promotional-material-type promotional-material-type.xml
material-id Provided by the applicant
issue-date Provided by the applicant
II. START OF THE MODULE 1 eCTD BACKBONE FILE

Name the Module 1 eCTD Backbone File us-regional.xml and place it in the us folder that is in the
folder named m1 as described in Providing Regulatory Submissions in Electronic Format —
Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
Specifications. For example, the path for the us-regional.xml file for sequence number 0006 is
0006/m1/us/us-regional.xml. Include a reference to a leaf element in the Module 2 to 5 eCTD
Backbone File (index.xml) for the us-regional.xml file. In the corresponding Module 2 to 5 eCTD
Backbone File, the operation attribute should have a value of “new.”
The header of the Module 1 eCTD Backbone File is always the same. It contains machine-readable
information about the following:
• Version of XML being used

• Type of characters that are allowed in the file
• Locations of the standards that control the organization of the file
The common header is provided below:
<?xml version="1.0" encoding="UTF-8" standalone="no"?>

<!DOCTYPE fda-regional:fda-regional SYSTEM "http://www.accessdata.fda.gov/static/eCTD/us-regional-v3-
3.dtd">
<?xml-stylesheet type="text/xsl" href="http://www.accessdata.fda.gov/static/eCTD/us-regional.xsl"?>
<fda-regional:fda-regional dtd-version=”3.3” xml:lang=”text” xmlns:fda-regional=”http://www.ich.org/fda”
xmlns:xlink=”http://www.w3c.org/1999/xlink”>
…
1
The 356h and 1571 forms are placed in their respective application’s admin section and other forms are placed in
the module 1 heading element m1-1-forms using the form element.
Version 2.3 2
All the heading elements and content for Module 1 should be provided after these elements and
before the last element closing tag named </fda-regional:fda-regional>.
III. ADMIN ELEMENTS

Administrative information is contained in the admin element, which is contained in the fda-
regional:fda-regional element. The admin element contains two child elements: applicant-info and
application-set. These elements should be placed in order as listed below.
…
<fda-regional:fda-regional>
<admin>
<applicant-info> </applicant-info>
<application-set> </application-set>
</admin>
<m1-regional>
</m1-regional>
</fda-regional:fda-regional>
…
A. Applicant-info Element
The applicant-info element contains the following child elements: id, company-name,
submission-description, and applicant-contacts.
1. ID Element
The id element is the Data Universal Numbering System (D-U-N-S®) number that is assigned and
maintained by Dun & Bradstreet. The nine (9)-digit D-U-N-S® number serves as a unique identifier
(code) of a business entity and it is increasingly being used as a resource for FDA to assure accurate
identification and to verify certain business information for that entity, e.g., trade names used by the
entity, and addresses; the number will supplement other identifiers such as the company-name
element. The D-U-N-S® number for the business entity that is the sponsor, applicant or holder of the
submission should be provided and if applicable, it should match that used in the User Fee system.
The same D-U-N-S® number should be used for all submissions to an application, unless there is a
change in ownership of the application. Provide this element with every submission.
2. Company-name Element
The sponsor or applicant’s name is located in the company-name element. An example of the
company-name element for the “Very Best Drug Company” is provided below:
…
<company-name>Very Best Drug Company</company-name>
…
Provide this element with every submission.
Version 2.3 3
3. Submission-description Element
The submission-description element is an optional field that allows up to 128 characters. Only the
first 128 characters of the submission description element will be displayed.
• The information in the submission-description element should be a high level description of

the purpose of the submission and also help differentiate between similar types of submissions.
• Some examples of helpful submission descriptions are listed below:
• Supplement provides for new manufacturing site

• New site for API manufacture, DSM Ltd, Groningen, NL
• Proposed indication of an efficacy supplement
• Pharmtox Information Amendment – Final Study Report A1001
• Clinical Information Amendment – New Protocol A001100
• Response to an IR letter and date
• Type of amendment (clinical – new protocol, clinical – protocol amendment,
pharmacology, toxicology, etc.)
• The field should not:

• contain a response to FDA inquiries
• replace the cover letter
• pose questions to the FDA
• contain information that is in support of an application or is needed in the
approvability or acceptability of an application, or
• contain information that is critical or needs to be reviewed.
4. Applicant-contacts Element
The applicant-contacts element contains one or more applicant-contact elements. Provide at least
one complete applicant-contact element with every submission. The elements contained in the
applicant-contact element are: applicant-contact-name, telephones, and emails. For the
applicant-contact-name element, include the applicant-contact-type attribute. The telephones
element contains a telephone element limited to 64 characters that requires the telephone-number-
type attribute. The emails element contains an email element limited to 64 characters that does not
require an attribute. When attributes are required, they should be provided as coded values from
their corresponding attribute list (applicant-contact-type.xml and telephone-number-type.xml). The
current valid codes for applicant-contact-type and telephone-number-type are available on the FDA
web site:
An example of the applicant-contacts element containing two applicant-contact elements is shown

below and includes: contact names, telephone numbers, email addresses and coded attributes. The
applicant-contact element below shows Jane Smith as a regulatory contact and John Smith as the
technical contact, with their respective example contact information:
….
<applicant-contacts>
Version 2.3 4
<applicant-contact>
<applicant-contact-name applicant-contact-type="fdaact1">Jane Smith</applicant-contact-name>
<telephones>
<telephone telephone-number-type="fdatnt1">1-212-555-1234</telephone>
</telephones>
<emails>
<email>[email protected]</email>
</emails>
</applicant-contact>
<applicant-contact>
<applicant-contact-name applicant-contact-type="fdaact2">John Smith</applicant-contact-name>
<telephones>
</telephones>
<emails>
<email>[email protected]</email>
</emails>
</applicant-contact>
</applicant-contacts>
…
B. Application-set Element
The application-set element may contain one or more application elements. This provides the
functionality to submit a single submission to more than one application, which is also referred to as
a “grouped submission” (refer to section IV. Grouped Submissions). If more than one application
element is provided, each application element must contain the application-information and
submission-information child elements.
Each application element has a required attribute of application-containing-files and requires a

value of either “true” or “false.” The purpose of the application-containing-files attribute is to
indicate the application number folder where files will be stored (refer to section IV. Grouped
Submissions). For a submission to only one application, this attribute value should be “true.”
For a grouped submission, a value of “true” should only be set in one application element.
The elements contained in the application element are application-information and

submission-information, and they should be included in order as listed here.
1. Application-information Element
The elements contained in the application-information element are application-number and
cross-reference-application-number.
a. Application-number element
Provide the six (6)-digit application number in the application-number element. Provide only
numeric digits, including any leading zeros for the application number, without letters or dashes.
Each application-number element requires an attribute of application-type, and the attribute should
be provided as a coded value from its corresponding attribute list (application-type.xml). The current
Version 2.3 5
valid codes for application-type are available on the FDA web site:
The following is an example of the application-number element for NDA 456789. In this example,
the application number contains the attribute value of “fdaat1” for the application-type, which
indicates it is a new drug application (NDA).
…
<application-number application-type="fdaat1 ">456789</application-number>
…
Provide this element and attribute with every application element in the submission.
b. Cross-reference-application-number element
This element should only be provided when an application makes reference to other applications.
Cross references are unnecessary when the application(s) being referenced are in the application-
set. 2 A cross reference only needs to be identified once.
Provide the six (6)-digit application number in the cross-reference-application-number element.

Only provide numeric digits, including any leading zeros for the application number, without letters
or dashes.
Each cross-reference-application-number element requires an attribute of application-type and the

attribute should be provided as a coded value from its corresponding attribute list
(application-type.xml). The current valid codes for application-type are available on the FDA web
site:
The following is an example of a cross-reference-application-number element. In this example, the

application NDA 456789 cross-references DMF 012345. The cross-reference-application-number
element contains the attribute value of “fdaat5” for the application-type, which indicates it is a Drug
Master File (DMF).
…
<application-number application-type="fdaat1">456789</application-number>
<cross-reference-application-number application-type="fdaat5">012345</cross-reference-application-number>
…
2
The cross reference electronically provides the same information found on the 356h and 1571 application forms.
Version 2.3 6
2. Submission-information element
The submission-information element contains three child elements: submission-id,
sequence-number, and form.
a. Submission-id element - <submission-id>

The submission-id element is used to identify each individual regulatory activity (original
application, supplement, annual report, etc.) in an application. All submissions that belong to a
specific regulatory activity (for example, a supplement and all amendments related to that
supplement) should contain the same four (4)-digit number in their submission-id element. The four
(4)-digit submission-id number for each regulatory activity is determined by the sequence-number
of the first submission to each new regulatory activity. The submission-id should match the four (4)-
digit sequence-number for that first submission to the new regulatory activity (refer to section
III.B.2.b. Sequence-number element and section III.B.3. Building Regulatory Activities for additional
details). Provide the four (4)-digit number in the submission-id element, including any leading
zeros.
The submission-id element contains two attributes: submission-type and supplement-effective-date-

type. The supplement-effective-date-type attribute is only required and applicable to the
submission types: efficacy supplement, labeling supplement, or chemistry manufacturing controls
supplement with a submission-sub-type of “application.” The attributes should be provided as coded
values from their corresponding attribute lists (submission-type.xml and supplement-effective-date-
type.xml). The current valid codes for submission-type and supplement-effective-date-type are
available on the FDA web site:
For the correct usage of submission-type and supplement-effective-date-type, refer to Tables 2 and 3
below. Table 2 provides the descriptions of use for each submission-type and Table 3 provides the
description and usage of each supplement-effective-date-type. When applying these attributes, it is
important to only use them according to the “valid for” sections provided in these tables.
Below is an example of a submission-id element for a labeling supplement to an application. This

submission-id element also includes the submission-type attribute and the supplement-effective-
date-type attribute. In this example, the submission-id is identified as “0009” (refer to section
III.B.3. Building Regulatory Activities for additional details on assigning the correct submission-id
number to each regulatory activity), it has a submission-type attribute code of “fdast4”: indicating
that the submission type is a labeling supplement, and it has a supplement-effective-date-type of
“fdasedt2”: indicating that it is a CBE-0 supplement.
…
<submission-id submission-type="fdast4" supplement-effective-date-type="fdasedt2">0009</submission-id>
…
b. Sequence-number Element - <sequence-number>

The sequence-number element is used to uniquely identify each individual submission to an
application. It must be a unique number with a maximum of four (4)-numeric digits, should start at
0001, and should not exceed 9999. The sequence-number should normally be incremented by one
Version 2.3 7
each time a submission is made to the application. The sequence-number element contains the
attribute submission-sub-type, used to further clarify the purpose of the submission. Only certain
submission-sub-type attributes are applicable to certain submission types. For the correct usage of
the submission-sub-type attribute, refer to Tables 2 and 4 below. These tables provide the
description for each submission-sub-type and outline the correct usage of submission sub-types for
each submission-type. The attribute should be provided as a coded value from its corresponding
attribute list (submission-sub-type.xml). The current valid codes for submission-sub-type are
available on the FDA web site:
In the example below, the sequence-number element contains “0004” indicating that it is the fourth
submission to the application and the submission-sub-type attribute contains the code of “fdasst4”
indicating that it is an amendment.
…
<sequence-number submission-sub-type="fdasst4">0004</sequence-number>
…
c. Form Element - <form>

To accommodate grouped submissions, certain forms should only be referenced in the form element
contained in the submission-information element. This will allow these forms to only display in
review tools under the specified application. The form element is further described in section VI.B.
M1 Forms and the form types with their designated reference locations are referenced in Table 10. 3
For all form leafs referenced in the form element or Module 1 heading element, the attribute of form-
type is required and indicates the type of form being referenced and submitted.
In the example below, the form-type attribute indicates the form is Form FDA 356h. Multiple leafs
can be provided for a form element in order to accommodate attachments (e.g. establishment
description information).
…
<form form-type="fdaft2">
<leaf ID="a11383b1215534dfdf8a81df05237f796" checksum="49e154b9bee040a2de43c459affd63e4"
checksum-type="md5" operation="new" xlink:href="356h-nda456789-0004.pdf" xlink:type="simple">
<title>Form FDA 356h - 0004 - Amendment to Original Application</title>
</leaf>
</form>
…
3
Refer to the current version of the form-type.xml for a complete list of forms.
Version 2.3 8
Table 2: Submission Types and Descriptions of Use

Supplement Effective Date Type (if
Submission Type Submission Valid For
applicable and submission-sub-type
Sub-Type Application Types
= “application”)
Original Application Presubmission IND, NDA, ANDA,
Application BLA, DMF, EUA
Amendment
Resubmission
Efficacy Supplement Presubmission NDA, BLA
Application Prior Approval Supplement (PAS)
Amendment
Resubmission
Chemistry Presubmission NDA, ANDA, BLA
Manufacturing
Controls Supplement Application Prior Approval Supplement (PAS),
Changes Being Effected (CBE-0), or
Changes Being Effected 30 (CBE-30)
Amendment
Resubmission
Labeling Supplement Presubmission NDA, ANDA, BLA
Application Prior Approval Supplement (PAS) or
Changes Being Effected (CBE-0)
Amendment
Resubmission
Annual Report Report IND, NDA, ANDA,
Amendment BLA, DMF
Product Correspondence IND, NDA, ANDA,
Correspondence Amendment BLA, DMF
Postmarketing Original NDA, BLA
Requirements or Amendment
Postmarketing
Commitments
Promotional Labeling Original NDA, ANDA, BLA
Advertising Resubmission
Amendment
IND Safety Reports Report IND
Amendment
Periodic Safety Report NDA, ANDA, BLA
Reports (Periodic Amendment
Adverse Drug
Experience Report
(PADER) or
Periodic Safety
Update Report
(PSUR))
Version 2.3 9
Table 3: Supplement-Effective-Date-Types and Descriptions of Use

Supplement Valid for Submission Types
Effective Date Description
Type
Prior Approval The Prior Approval Supplement is a supplement Efficacy Supplement,
Supplement submission for a major change for which distribution Chemistry Manufacturing
(PAS) of the product made using the change cannot occur Controls Supplement,
prior to FDA approval as provided for in 21 CFR Labeling Supplement
314.70 and 21 CFR 601.12(b).
Changes Being The “Changes Being Effected” is a supplement Chemistry Manufacturing
Effected submission for certain moderate changes for which Controls Supplement,
(CBE-0) distribution can occur when FDA receives the Labeling Supplement
supplement as provided for in 21 CFR 314.70 and 21
CFR 601.12(c)(5).
Changes Being The “Changes Being Effected in 30 Days” is a Chemistry Manufacturing
Effected 30 supplement submission for certain moderate changes Controls Supplement
(CBE-30) that must be submitted to FDA at least 30 days
before the distribution of the product made using the
change as provided for in 21 CFR 314.70 and 21
CFR 601.12(c).
Table 4: Submission Sub-Types and Descriptions of Use

Submission Valid For the Listed
Sub-Type Description Submission Types
Presubmission A submission to the Agency that occurs prior to the Original Application,
actual submission of a full application (e.g., rolling Efficacy Supplement,
review, reviewable unit, clinical information that the Chemistry Manufacturing
applicant requests comment on prior to submitting Controls Supplement,
their application). Not all applications will have Labeling Supplement
presubmissions.
Application The submission that represents the application’s Original Application,
primary supportive material. There should only be Efficacy Supplement,
one submission with a sub-type of application within Chemistry Manufacturing
a given submission group. Controls Supplement,
Labeling Supplement
Amendment A submission that contains additional supportive Original Application,

material to augment information previously Efficacy Supplement,
submitted. Examples include responses to Chemistry Manufacturing
information requests, additional draft labeling during Controls Supplement,
negotiations, etc. Annual Report,
Product Correspondence,
Postmarketing Requirements or
Postmarketing Commitments,
Promotional Labeling
Version 2.3 10
Submission Valid For the Listed

Sub-Type Description Submission Types
Advertising,
IND Safety Reports,
Periodic Safety Reports
(Periodic Adverse Drug
Experience Report (PADER) or
Periodic Safety Update Report
(PSUR))
Resubmission A submission that contains additional information Original Application,
for the Agency to consider following the issuance of Efficacy Supplement,
an action communication to the applicant (e.g., Chemistry Manufacturing
complete response or inactivation). Controls Supplement,
For promotional labeling and advertising, the Labeling Supplement,
submission of revised promotional materials that Promotional Labeling
were previously submitted as an original submission Advertising
sub-type. Includes requests for advisory on launch
materials, requests for advisory on nonlaunch
materials, pre-submission of promotional materials
for accelerated approval products, and materials
submitted under the Pre-Dissemination Review of
Television Ads Program.
Report A submission that contains a new annual report, IND Annual Report,
Safety Report, or Periodic Safety Report (Periodic IND Safety Reports,
Adverse Drug Experience Report (PADER) or Periodic Safety Reports
Periodic Safety Update Report (PSUR)). (Periodic Adverse Drug
Experience Report (PADER) or
Periodic Safety Update Report
(PSUR))
Original Submission of original promotional materials Promotional Labeling
including all promotional labeling and advertising Advertising,
submissions, or Postmarketing Requirements or Postmarketing Requirements or
Postmarketing Commitments Postmarketing Commitments
Correspondence Routine: administrative changes, e.g., change of Product Correspondence
address, authorized official, or meeting requests.
Donor re-entry request: An applicant’s request to
re-enter a deferred donor when regulations and/or
guidance do not provide a qualification method or
process for their specific situation. (21 CFR
610.41(b))
License re-issuance: request from applicant to
change legal name.
Lot distribution report: Postmarketing report
required by 21 CFR 600.81 to be submitted every six
(6) months upon approval/licensing of vaccine or
biologic product.
Final labeling
Version 2.3 11
3. Building Regulatory Activities

A regulatory activity is established, defined and identified by the submission type in an eCTD
application. The purpose could be a notification of a change or a request to approve a new product or
change. There can be one or more regulatory activities within an application and each regulatory
activity can consist of one or more submissions.
The first submission to a regulatory activity establishes the submission-id that will be used in
subsequent submissions for the same regulatory activity in an application. Using the same
submission-id number for a regulatory activity allows the related submissions to be grouped together
for that regulatory activity. In an eCTD submission, the submission-id element and submission-type
attribute are used to group regulatory activities; the sequence-number element and submission sub-
type attribute are used to indicate the order of submissions submitted for the same regulatory activity.
All submissions related to a single regulatory activity should be grouped together. This is
accomplished by using the submission-id number. The number used in the submission-id element is
determined by the sequence-number of the first submission to each regulatory activity. For
example, if the original application is sequence-number 0001, then the submission-id for that
regulatory activity is also 0001. When an amendment is submitted to this original application, the
submission-id 0001 is used (to show the submissions are related), while the sequence-number is
incremented by one for each subsequent submission (refer to Scenario 1 below).
The following two scenarios demonstrate the use of submission-id, submission-type, sequence-
number and submission-sub-type:
Scenario 1: In this scenario, an applicant is submitting the first submission to the original
application. The submission-id should match the sequence-number since it is the first submission
for this regulatory activity (original application). The submission-id and
sequence-number should both contain “0001,” and the appropriate submission-type code is used to
indicate that it is an original application. All submissions that relate to this original application
(regulatory activity) should contain the same submission-id of “0001.”
Table 5: Building Regulatory Activities – Scenario 1
The Original Application regulatory activity consists of two presubmissions, the original
application, and two amendments and is identified by the submission-id number “0001.”
Presubmission (meeting request)
submission-id 0001
submission-type attribute fdast1 (Original Application)
sequence-number 0001
submission-sub-type attribute fdasst2 (presubmission)
Presubmission (meeting package)
submission-id 0001
Original Application
submission-id 0001
Version 2.3 12
submission-sub-type attribute fdasst3 (application)

Amendment #1
submission-id 0001
submission-sub-type attribute fdasst4 (amendment)
Amendment #2
submission-id 0001
Scenario 2: In this second scenario, the first submission for a new efficacy supplement (a new
regulatory activity) is submitted to an application; therefore, the number used for the submission-id
should match the sequence-number. Since the sequence-number is incremented within the
application for each submission and the last sequence number submitted to the application was
“0005,” both the submission-id and the sequence-number for this new efficacy supplement will be
“0006.” This submission and all subsequent submissions that relate to this efficacy supplement will
use submission-id “0006.” The submission-type code indicating it is an efficacy supplement is
used for the supplement and also for all sequences related to the supplement. The submission-sub-
type attribute is used (as indicated in Tables 2 and 4 above) to further clarify the purpose of each
submission. The supplement-effective-date-type indicates it is a Prior Approval Supplement (PAS
as indicated in Tables 2 and 3 above)
Table 6: Building Regulatory Activities – Scenario 2

The Efficacy Supplement regulatory activity below consists of three submissions and is identified
by a submission-id number of “0006.”
Efficacy Supplement (new indication)
submission-id 0006
submission-type attribute fdast2 (Efficacy Supplement)
supplement-effective-date-type attribute fdasedt1 (Prior Approval Supplement (PAS))
Amendment #1 to Efficacy Supplement
submission-id 0006
Amendment #2 to Efficacy Supplement
submission-id 0006
IV. Grouped Submissions

A grouped submission is a single sequence containing a us-regional.xml, index.xml and any other
Version 2.3 13
applicable files applied to more than one application. A grouped submission is also known as a
global supplement, global submission, bundled supplement, bundled submission, multiple product
submission or trans-BLA. This type of submission eliminates the need to submit multiple, identical
submissions to different applications. The files referenced in the grouped submission are applied to
all applications indentified. The grouped submission concept does not replace or affect previously
existing cross-referencing functionality (use of m1-4-4 or cross application reference links).
The files referenced in the XML backbones will physically reside in the application folder indicated
with a value of “true” for the application-containing-files attribute. Only one application element in
a grouped submission should contain a value of “true” for the application-containing-files attribute.
The application whose application-containing-files attribute has a value of “true” is considered the
primary application and should remain constant in future sequences.
When referencing or modifying files that were submitted in a grouped submission, it is possible that
the files being referenced are not located in the same application type/number folder as the “new”
files being submitted. In this case, the modified-file leaf attribute must also include the correct
application type/number folder where the files are physically stored (refer to section V. Leaf
Element).
The following items listed below provide general information and use limitations for submitting a
grouped submission to multiple applications 4:
General Information:
• Initial grouped submissions should only include new leaves.
• When using lifecycle operations of append, delete, or replace in a subsequent grouped
submission, the lifecycle operation will apply to the modified leaf in all submissions
referenced in the application set.
• The grouped submission’s content must reside in the same exact eCTD location for all
applications included in the grouped.
Use Limitations:
• Only one application type can be used in a grouped submission.
• Only one submission type can be used in a grouped submission.
• Grouped submissions are only supported using DTD version 3.3 or higher.
Table 7: Grouped Submissions Limitations and Use

Center Acceptance of
Application Types
Submission Types Allowed Grouped Submission
Allowed
CDER CBER
ANDA Labeling Supplement, YES NO
Chemistry Manufacturing Controls Supplement,
Promotional Labeling Advertising
BLA Efficacy Supplement, YES YES
4 Electronic consideration(s) for grouped submissions will not supersede the policy and practice of bundled
submissions as it may or may not affect user fees per the Guidance for Industry: Guidance for Industry Submitting
Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees.
Version 2.3 14
Center Acceptance of
Application Types
Submission Types Allowed Grouped Submission
Allowed
CDER CBER
Labeling Supplement,
DMF Product Correspondence YES NO
IND Annual Report, YES NO
Product Correspondence
NDA Efficacy Supplement, YES NO
Labeling Supplement,
The following two scenarios demonstrate a grouped submission for a Labeling Supplement
regulatory activity to three (3) applications and an amendment to the Labeling Supplement. The
scenarios also show the use of the supplement-effective-date-type attribute for the Labeling
Supplement.
Table 8: Grouped Submission – Scenario 1

Grouped Submission Scenario 1: A grouped submission for a Labeling Supplement is being
submitted to NDA 456789, 567890, and 678901. All the new files submitted are contained in
the folder for NDA 456789, sequence 0011.
NDA 456789
application-containing-files true
submission-id 0011
submission-type attribute fdast4 Labeling Supplement
supplement-effective-date-type attribute fdasedt2 (CBE-0)
NDA 567890
application-containing-files false
submission-id 0014
NDA 678901
submission-id 0012
Version 2.3 15
Table 9: Grouped Submission – Scenario 2

Grouped Submission Scenario 2: An amendment is being submitted to the Labeling
Supplement previously submitted as a grouped submission. Any life cycle operations on
files will affect all applications indicated in the application-set. All the new files submitted
are contained in the folder for NDA 456789, sequence 0012.
NDA 456789
application-containing-files true
submission-id 0011
NDA 567890
submission-id 0014
NDA 678901
submission-id 0012
V. LEAF ELEMENT
Information for an individual document is contained in the leaf element, its attributes, and its title
element. The leaf element is used repeatedly throughout the eCTD backbone files to provide
individual information for each document being submitted. Detailed descriptions of each part of the
leaf element and how to use them are found in the document, The eCTD Backbone File Specification
for Modules 2 through 5. When preparing the us-regional.xml file, the xlink:href and modified-file
leaf attributes should reflect the path relative to the location of the us-regional.xml file location in the
submission. The following is an example of a xlink:href attribute and its value for the 356h.pdf in
Module 1 in the same submission:
…
xlink:href="356h.pdf"
…
The following is an example of a modified-file leaf attribute and its value in Module 1 in an earlier
submission:
…
modified-file="../../../0001/m1/us/us-regional.xml#id34567"
…
The following is an example of a modified-file leaf attribute which is modifying a leaf that was
previously submitted to a different application which contained the file. The modified-file path
includes the application number for the application which contained the previously submitted file and
Version 2.3 16
had an application-containing-files element value of “true”. In order to perform life cycle operations
on leafs previously submitted in a grouped submission, the modified-file path references the
application number, sequence number, and leaf id for the application where the leaf was originally
submitted with the application-containing-files element value indicating “true.”
…
modified-file="../../../../nda456789/0001/m1/us/us-regional.xml#id21342"
…
VI. SECTION HEADING ELEMENTS FOR MODULE 1

This section describes the heading elements relevant to Module 1. This is the equivalent to the
heading elements described in the document titled, The eCTD Backbone File Specification for
Modules 2 through 5.
The Module 1 section heading elements are listed in the DTD. For information on the placement of
content in these headings, please refer to The Comprehensive Table of Contents Headings and
Hierarchy. Leaf elements should only be referenced at the lowest level section/sub-section of the
hierarchy for each heading element. If a section heading does not contain references to files or
documents, omit the element for that heading in the eCTD backbone file.
A. M1 Regional Section Headings Requiring Attributes
Certain Module 1 heading elements require the use of an attribute to describe the information
referenced in those sections. The heading elements that require an attribute are provided below:
• the form element under m1-1-forms requires an attribute indicating the form-type <attribute =
form-type>
• m1-15-promotional-material requires an attribute to indicate the promotional-material-
audience-type <attribute = promotional-material-audience-type>
• m1-15-2-materials requires an attribute to indicate the purpose of the promotional submission
<attribute = promotional-material-doc-type>
• m1-15-2-1-material requires attributes to indicate the type of media/delivery method of the
promotional material, the applicant’s identifier for the material and the date of the initial
dissemination of the promotional labeling or the date of initial publication for an advertisement
(only provided when the promotional-material-doc-type is a promotional 2253 submission)
<attribute = promotional-material-type, material-id, and issue-date>.
B. M1 Forms
The m1-1-forms heading element contains the form element. When a leaf is placed under the form
element, an attribute is required and is used to indicate the type of form being submitted. Each form
element requires an attribute of form-type and the attribute should be provided as a coded value from
its corresponding attribute list (form-type.xml). Multiple leafs can be provided for a form element in
order to accommodate attachments.
The current valid codes for form-type are available on the FDA web site:
Version 2.3 17
In the example below, the form-type attribute indicates the coded value for the Form FDA 2253.
…
<m1-1-forms>
<form form-type="fdaft5">
<leaf ID=" a11383b1215534dfdf8a81em95237f796"
checksum="49e154b9bee094a2de43c459affd63e4" checksum-type="md5" operation="new"
xlink:href="2253-nda456789-0016.pdf" xlink:type="simple">
<title>Form 2253 Professional sales aid 20120415</title>
</leaf>
</form>
</m1-1-forms>
…
Table 10: Form Types and eCTD Location

Form Type Reference Location
Form FDA 1571: Investigational New Drug Application form element within the submission-
(IND) information element
Form FDA 356h: Application to Market a New Drug, form element within the submission-
Biologic, or an Antibiotic Drug for Human Use” information element
Patent Forms (Form FDA3542a and Form FDA 3542) m1-3-5-1-patent-information
element within the m1-3-5-patent-
and-exclusivity element
All other forms 5 form element within the m1-1-forms
element
C. Module 1.15 — Promotional Material
When providing information in Module 1.15, the leaves should be referenced at the lowest heading
elements. The m1-15-promotional-material heading element requires an attribute of promotional-
material-audience-type. When a leaf is referenced in any subsection of Module 1.15, the attribute
must be provided as a coded value from its corresponding attribute list (promotional-material-
audience-type.xml). The current valid codes for promotional-material-audience-type are available
on the FDA web site:
When providing information in a subsection of Module 1.15.2 Materials, three attributes are
required: promotional-material-doc-type, promotional-material-type, and material-id. An
additional optional attribute, issue-date, should only be provided when the promotional-material-
doc-type is a promotional 2253 submission. The attribute promotional-material-doc-type should be
provided with the m1-15-2-materials heading element and the attributes promotional-material-type,
material-id, and issue-date (if applicable) should be provided with the m-1-15-2-1 material heading
element. The attributes for promotional-material-doc-type and promotional-material-type should be
provided as coded values from their corresponding attribute list (promotional-material-doc-type.xml
and promotional-material-type.xml). The material-id attribute may consist of alpha and/or numeric
5
Refer to the current version of the form-type.xml for a complete list of forms.
Version 2.3 18
characters and should not exceed 30 characters. The issue-date attribute, if applicable, should follow
the date format as yyyymmdd (4-digit year, 2-digit month, and 2-digit day). The current valid codes
for promotional-material-doc-type and promotional-material-type are available on the FDA web
site:
In the example below, the promotional-material-audience-type indicates the promotional material is

intended for healthcare professionals, the promotional-material-doc-type indicates that the
submission is a Form FDA 2253 submission, the promotional-material-type indicates the material
being submitted is a sales aid, the material-id provided by the applicant is “65no35482”, and the
issue-date provided by the applicant is “20120415” (April 15, 2012 formatted as yyyymmdd).
…
<m1-15-promotional-material promotional-material-audience-type="fdapmat2">
<m1-15-2-materials promotional-material-doc-type="fdapmdt1">
<m1-15-2-1-material promotional-material-type="fdapmt25" material-id=”65no35482” issue-
date=”20120415”>
<m1-15-2-1-1-clean-version>
<leaf ID="b21383b1215534dfdf8a81df05237f704"
checksum="49e154b9bee040a2de43c459affd6304" checksum-type="md5"
operation="new" xlink:href="clean-sales-aid.pdf" xlink:type="simple">
<title> SALES AID 65NO35482 Considerations for treatment 20120415</title>
</leaf>
</m1-15-2-1-1-clean-version>
</m1-15-2-1-material>
</m1-15-2-materials>
</m1-15-promotional-material>
…
Table 11: Promotional Material Audience Types and Descriptions

Promotional Material Description
Audience Type
Consumer Promotional materials directed to consumers
Professional Promotional materials directed to health care professionals
Table 12: Promotional Material Doc Types and Descriptions
Promotional Material Description

Document Type
Promotional 2253 Form and materials required from submitter at first publication of
marketing and advertising materials
Request for Advisory Voluntary submission of launch promotional materials for FDA
Launch review and comment sent prior to dissemination/publication
Request for Advisory Voluntary submission of promotional materials for FDA review and
Non-Launch comment sent prior to dissemination/publication
Pre-submission Promotional materials intended to be used in the first 120 days after
Accelerated Launch approval that are submitted to FDA prior to
Version 2.3 19
dissemination/publication as required by 21 CFR 314.550 and 601.45

Pre-submission Promotional materials intended to be used after the 120-day post
Accelerated Non-Launch approval period that are submitted to FDA prior to
dissemination/publication as required by 21 CFR 314.550 and 601.45
Pre-Dissemination Television advertisements submitted to FDA under the Pre-
Review of Television Ads Dissemination Review of Television Ads Program
Table 13: Material ID and Issue Date Descriptions
M1-15-2-1 Description
Applicant
Defined
Attributes
Material ID The applicant's identification code or other designation of the

specific promotional material. The material-id may consist of
alpha and/or numeric characters and has a 30 character limitation.
Issue date The date of the initial dissemination of the promotional labeling or the
date of initial publication for an advertisement. The format of the date
should be YYYYMMDD.
Version 2.3 20
APPENDIX 1: M1 Document Type Definition (DTD) Version 3.3

<?xml version="1.0" encoding="UTF-8"?>



<!ELEMENT fda-regional:fda-regional (admin, m1-regional?)>
<!ATTLIST fda-regional:fda-regional
xmlns:fda-regional CDATA #FIXED "http://www.ich.org/fda"
xmlns:xlink CDATA #FIXED "http://www.w3c.org/1999/xlink"
xml:lang CDATA #IMPLIED
dtd-version CDATA #FIXED "3.3"
>
<!ELEMENT leaf (title, link-text?)>
<!ATTLIST leaf
ID ID #REQUIRED
application-version CDATA #IMPLIED
version CDATA #IMPLIED
font-library CDATA #IMPLIED
operation (delete | new | append | replace) #REQUIRED
modified-file CDATA #IMPLIED
checksum CDATA #IMPLIED
checksum-type CDATA #IMPLIED
keywords CDATA #IMPLIED
xlink:type CDATA #FIXED "simple"
xlink:role CDATA #IMPLIED
xlink:href CDATA #IMPLIED
xlink:show (embed | none | other | new | replace) #IMPLIED
xlink:actuate (onLoad | none | other | onRequest) #IMPLIED
>
<!ELEMENT title (#PCDATA)>
<!ATTLIST title
ID ID #IMPLIED
>
<!ELEMENT link-text (#PCDATA | xref)*>
<!ATTLIST link-text
ID ID #IMPLIED
>
<!ELEMENT xref EMPTY>
<!ATTLIST xref
ID ID #IMPLIED
xlink:title CDATA #REQUIRED
xlink:href CDATA #REQUIRED
Version 2.3 21
xlink:show (embed | none | other | new | replace) #IMPLIED

xlink:actuate (onLoad | none | other | onRequest) #IMPLIED
>
<!ELEMENT node-extension (title, (leaf | node-extension)+)>
<!ATTLIST node-extension
ID ID #IMPLIED
>
<!ELEMENT admin (applicant-info, application-set)>
<!ELEMENT applicant-info (id, company-name, submission-description?, applicant-contacts)>
<!ELEMENT id (#PCDATA)>
<!ELEMENT company-name (#PCDATA)>
<!ELEMENT submission-description (#PCDATA)>
<!ELEMENT applicant-contacts (applicant-contact+)>
<!ELEMENT applicant-contact (applicant-contact-name, telephones, emails)>
<!ELEMENT applicant-contact-name (#PCDATA)>
<!ATTLIST applicant-contact-name
applicant-contact-type CDATA #REQUIRED
>
<!ELEMENT telephones (telephone+)>
<!ELEMENT telephone (#PCDATA)>
<!ATTLIST telephone
telephone-number-type CDATA #REQUIRED
>
<!ELEMENT emails (email+)>
<!ELEMENT email (#PCDATA)>
<!ELEMENT application-set (application+)>
<!ELEMENT application (application-information, submission-information)>
<!ATTLIST application
application-containing-files (false | true) #REQUIRED
>
<!ELEMENT application-information (application-number, cross-reference-application-
number*)>
<!ELEMENT application-number (#PCDATA)>
<!ATTLIST application-number
application-type CDATA #REQUIRED
>
<!ELEMENT cross-reference-application-number (#PCDATA)>
<!ATTLIST cross-reference-application-number
application-type CDATA #REQUIRED
>
<!ELEMENT submission-information (submission-id, sequence-number, form?)>
<!ELEMENT submission-id (#PCDATA)>
<!ATTLIST submission-id
submission-type CDATA #REQUIRED
supplement-effective-date-type CDATA #IMPLIED
Version 2.3 22
>
<!ELEMENT sequence-number (#PCDATA)>
<!ATTLIST sequence-number
submission-sub-type CDATA #REQUIRED
>
<!ELEMENT form ((leaf | node-extension)*)>
<!ATTLIST form
form-type CDATA #REQUIRED
>
<!ELEMENT m1-regional (m1-1-forms?, m1-2-cover-letters?, m1-3-administrative-
information?, m1-4-references?, m1-5-application-status?, m1-6-meetings?, m1-7-fast-track?,
m1-8-special-protocol-assessment-request?, m1-9-pediatric-administrative-information?, m1-10-
dispute-resolution?, m1-11-information-amendment-information-not-covered-under-modules-2-
to-5?, m1-12-other-correspondence?, m1-13-annual-report?, m1-14-labeling?, m1-15-
promotional-material?, m1-16-risk-management-plan?, m1-17-postmarketing-studies?, m1-18-
proprietary-names?, m1-19-pre-eua-and-eua?, m1-20-general-investigational-plan-for-initial-
ind?)>
<!ATTLIST m1-regional
ID ID #IMPLIED
>
<!ELEMENT m1-1-forms (form*)>
<!ELEMENT m1-2-cover-letters ((leaf | node-extension)*)>
<!ATTLIST m1-2-cover-letters
ID ID #IMPLIED
>
<!ELEMENT m1-3-administrative-information (m1-3-1-contact-sponsor-applicant-
information*, m1-3-2-field-copy-certification*, m1-3-3-debarment-certification*, m1-3-4-
financial-certification-and-disclosure*, m1-3-5-patent-and-exclusivity*, m1-3-6-tropical-disease-
priority-review-voucher*)>
<!ATTLIST m1-3-administrative-information
ID ID #IMPLIED
>
<!ELEMENT m1-3-1-contact-sponsor-applicant-information (m1-3-1-1-change-of-address-or-
corporate-name*, m1-3-1-2-change-in-contact-agent*, m1-3-1-3-change-in-sponsor*, m1-3-1-4-
transfer-of-obligation*, m1-3-1-5-change-in-ownership-of-an-application-or-reissuance-of-
license*)>
<!ATTLIST m1-3-1-contact-sponsor-applicant-information
ID ID #IMPLIED
>
<!ELEMENT m1-3-1-1-change-of-address-or-corporate-name ((leaf | node-extension)*)>
<!ATTLIST m1-3-1-1-change-of-address-or-corporate-name
ID ID #IMPLIED
Version 2.3 23

>
<!ELEMENT m1-3-1-2-change-in-contact-agent ((leaf | node-extension)*)>
<!ATTLIST m1-3-1-2-change-in-contact-agent
ID ID #IMPLIED
>
<!ELEMENT m1-3-1-3-change-in-sponsor ((leaf | node-extension)*)>
<!ATTLIST m1-3-1-3-change-in-sponsor
ID ID #IMPLIED
>
<!ELEMENT m1-3-1-4-transfer-of-obligation ((leaf | node-extension)*)>
<!ATTLIST m1-3-1-4-transfer-of-obligation
ID ID #IMPLIED
>
<!ELEMENT m1-3-1-5-change-in-ownership-of-an-application-or-reissuance-of-license ((leaf |
node-extension)*)>
<!ATTLIST m1-3-1-5-change-in-ownership-of-an-application-or-reissuance-of-license
ID ID #IMPLIED
>
<!ELEMENT m1-3-2-field-copy-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-2-field-copy-certification
ID ID #IMPLIED
>
<!ELEMENT m1-3-3-debarment-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-3-debarment-certification
ID ID #IMPLIED
>
<!ELEMENT m1-3-4-financial-certification-and-disclosure ((leaf | node-extension)*)>
<!ATTLIST m1-3-4-financial-certification-and-disclosure
ID ID #IMPLIED
>
<!ELEMENT m1-3-5-patent-and-exclusivity (m1-3-5-1-patent-information*, m1-3-5-2-patent-
certification*, m1-3-5-3-exclusivity-claim*)>
<!ATTLIST m1-3-5-patent-and-exclusivity
ID ID #IMPLIED
>
<!ELEMENT m1-3-5-1-patent-information ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-1-patent-information
Version 2.3 24
ID ID #IMPLIED
>
<!ELEMENT m1-3-5-2-patent-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-2-patent-certification
ID ID #IMPLIED
>
<!ELEMENT m1-3-5-3-exclusivity-claim ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-3-exclusivity-claim
ID ID #IMPLIED
>
<!ELEMENT m1-3-6-tropical-disease-priority-review-voucher ((leaf | node-extension)*)>
<!ATTLIST m1-3-6-tropical-disease-priority-review-voucher
ID ID #IMPLIED
>
<!ELEMENT m1-4-references (m1-4-1-letter-of-authorization*, m1-4-2-statement-of-right-of-
reference*, m1-4-3-list-of-authorized-persons-to-incorporate-by-reference*, m1-4-4-cross-
reference-to-previously-submitted-information*)>
<!ATTLIST m1-4-references
ID ID #IMPLIED
>
<!ELEMENT m1-4-1-letter-of-authorization ((leaf | node-extension)*)>
<!ATTLIST m1-4-1-letter-of-authorization
ID ID #IMPLIED
>
<!ELEMENT m1-4-2-statement-of-right-of-reference ((leaf | node-extension)*)>
<!ATTLIST m1-4-2-statement-of-right-of-reference
ID ID #IMPLIED
>
<!ELEMENT m1-4-3-list-of-authorized-persons-to-incorporate-by-reference ((leaf | node-
extension)*)>
<!ATTLIST m1-4-3-list-of-authorized-persons-to-incorporate-by-reference
ID ID #IMPLIED
>
<!ELEMENT m1-4-4-cross-reference-to-previously-submitted-information ((leaf | node-
extension)*)>
<!ATTLIST m1-4-4-cross-reference-to-previously-submitted-information
ID ID #IMPLIED
Version 2.3 25
>
<!ELEMENT m1-5-application-status (m1-5-1-withdrawal-of-an-ind*, m1-5-2-inactivation-
request*, m1-5-3-reactivation-request*, m1-5-4-reinstatement-request*, m1-5-5-withdrawal-of-
an-unapproved-bla-nda-anda-or-supplement*, m1-5-6-withdrawal-of-listed-drug*, m1-5-7-
withdrawal-of-approval-of-an-application-or-revocation-of-license*)>
<!ATTLIST m1-5-application-status
ID ID #IMPLIED
>
<!ELEMENT m1-5-1-withdrawal-of-an-ind ((leaf | node-extension)*)>
<!ATTLIST m1-5-1-withdrawal-of-an-ind
ID ID #IMPLIED
>
<!ELEMENT m1-5-2-inactivation-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-2-inactivation-request
ID ID #IMPLIED
>
<!ELEMENT m1-5-3-reactivation-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-3-reactivation-request
ID ID #IMPLIED
>
<!ELEMENT m1-5-4-reinstatement-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-4-reinstatement-request
ID ID #IMPLIED
>
<!ELEMENT m1-5-5-withdrawal-of-an-unapproved-bla-nda-anda-or-supplement ((leaf | node-
extension)*)>
<!ATTLIST m1-5-5-withdrawal-of-an-unapproved-bla-nda-anda-or-supplement
ID ID #IMPLIED
>
<!ELEMENT m1-5-6-withdrawal-of-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-5-6-withdrawal-of-listed-drug
ID ID #IMPLIED
>
<!ELEMENT m1-5-7-withdrawal-of-approval-of-an-application-or-revocation-of-license ((leaf |
node-extension)*)>
<!ATTLIST m1-5-7-withdrawal-of-approval-of-an-application-or-revocation-of-license
ID ID #IMPLIED
>
Version 2.3 26
<!ELEMENT m1-6-meetings (m1-6-1-meeting-request*, m1-6-2-meeting-background-

materials*, m1-6-3-correspondence-regarding-meetings*)>
<!ATTLIST m1-6-meetings
ID ID #IMPLIED
>
<!ELEMENT m1-6-1-meeting-request ((leaf | node-extension)*)>
<!ATTLIST m1-6-1-meeting-request
ID ID #IMPLIED
>
<!ELEMENT m1-6-2-meeting-background-materials ((leaf | node-extension)*)>
<!ATTLIST m1-6-2-meeting-background-materials
ID ID #IMPLIED
>
<!ELEMENT m1-6-3-correspondence-regarding-meetings ((leaf | node-extension)*)>
<!ATTLIST m1-6-3-correspondence-regarding-meetings
ID ID #IMPLIED
>
<!ELEMENT m1-7-fast-track (m1-7-1-fast-track-designation-request*, m1-7-2-fast-track-
designation-withdrawal-request*, m1-7-3-rolling-review-request*, m1-7-4-correspondence-
regarding-fast-track-rolling-review*)>
<!ATTLIST m1-7-fast-track
ID ID #IMPLIED
>
<!ELEMENT m1-7-1-fast-track-designation-request ((leaf | node-extension)*)>
<!ATTLIST m1-7-1-fast-track-designation-request
ID ID #IMPLIED
>
<!ELEMENT m1-7-2-fast-track-designation-withdrawal-request ((leaf | node-extension)*)>
<!ATTLIST m1-7-2-fast-track-designation-withdrawal-request
ID ID #IMPLIED
>
<!ELEMENT m1-7-3-rolling-review-request ((leaf | node-extension)*)>
<!ATTLIST m1-7-3-rolling-review-request
ID ID #IMPLIED
>
<!ELEMENT m1-7-4-correspondence-regarding-fast-track-rolling-review ((leaf | node-
extension)*)>
<!ATTLIST m1-7-4-correspondence-regarding-fast-track-rolling-review
Version 2.3 27
ID ID #IMPLIED
>
<!ELEMENT m1-8-special-protocol-assessment-request (m1-8-1-clinical-study*, m1-8-2-
carcinogenicity-study*, m1-8-3-stability-study*, m1-8-4-animal-efficacy-study-for-approval-
under-the-animal-rule*)>
<!ATTLIST m1-8-special-protocol-assessment-request
ID ID #IMPLIED
>
<!ELEMENT m1-8-1-clinical-study ((leaf | node-extension)*)>
<!ATTLIST m1-8-1-clinical-study
ID ID #IMPLIED
>
<!ELEMENT m1-8-2-carcinogenicity-study ((leaf | node-extension)*)>
<!ATTLIST m1-8-2-carcinogenicity-study
ID ID #IMPLIED
>
<!ELEMENT m1-8-3-stability-study ((leaf | node-extension)*)>
<!ATTLIST m1-8-3-stability-study
ID ID #IMPLIED
>
<!ELEMENT m1-8-4-animal-efficacy-study-for-approval-under-the-animal-rule ((leaf | node-
extension)*)>
<!ATTLIST m1-8-4-animal-efficacy-study-for-approval-under-the-animal-rule
ID ID #IMPLIED
>
<!ELEMENT m1-9-pediatric-administrative-information (m1-9-1-request-for-waiver-of-
pediatric-studies*, m1-9-2-request-for-deferral-of-pediatric-studies*, m1-9-3-request-for-
pediatric-exclusivity-determination*, m1-9-4-proposed-pediatric-study-request-and-
amendments*, m1-9-6-other-correspondence-regarding-pediatric-exclusivity-or-study-plans*)>
<!ATTLIST m1-9-pediatric-administrative-information
ID ID #IMPLIED
>
<!ELEMENT m1-9-1-request-for-waiver-of-pediatric-studies ((leaf | node-extension)*)>
<!ATTLIST m1-9-1-request-for-waiver-of-pediatric-studies
ID ID #IMPLIED
>
<!ELEMENT m1-9-2-request-for-deferral-of-pediatric-studies ((leaf | node-extension)*)>
<!ATTLIST m1-9-2-request-for-deferral-of-pediatric-studies
Version 2.3 28
ID ID #IMPLIED
>
<!ELEMENT m1-9-3-request-for-pediatric-exclusivity-determination ((leaf | node-extension)*)>
<!ATTLIST m1-9-3-request-for-pediatric-exclusivity-determination
ID ID #IMPLIED
>
<!ELEMENT m1-9-4-proposed-pediatric-study-request-and-amendments ((leaf | node-
extension)*)>
<!ATTLIST m1-9-4-proposed-pediatric-study-request-and-amendments
ID ID #IMPLIED
>
<!ELEMENT m1-9-6-other-correspondence-regarding-pediatric-exclusivity-or-study-plans ((leaf
| node-extension)*)>
<!ATTLIST m1-9-6-other-correspondence-regarding-pediatric-exclusivity-or-study-plans
ID ID #IMPLIED
>
<!ELEMENT m1-10-dispute-resolution (m1-10-1-request-for-dispute-resolution*, m1-10-2-
correspondence-related-to-dispute-resolution*)>
<!ATTLIST m1-10-dispute-resolution
ID ID #IMPLIED
>
<!ELEMENT m1-10-1-request-for-dispute-resolution ((leaf | node-extension)*)>
<!ATTLIST m1-10-1-request-for-dispute-resolution
ID ID #IMPLIED
>
<!ELEMENT m1-10-2-correspondence-related-to-dispute-resolution ((leaf | node-extension)*)>
<!ATTLIST m1-10-2-correspondence-related-to-dispute-resolution
ID ID #IMPLIED
>
<!ELEMENT m1-11-information-amendment-information-not-covered-under-modules-2-to-5
(m1-11-1-quality-information-amendment*, m1-11-2-nonclinical-information-amendment*, m1-
11-3-clinical-information-amendment*, m1-11-4-multiple-module-information-amendment*)>
<!ATTLIST m1-11-information-amendment-information-not-covered-under-modules-2-to-5
ID ID #IMPLIED
>
<!ELEMENT m1-11-1-quality-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-1-quality-information-amendment
ID ID #IMPLIED
Version 2.3 29

>
<!ELEMENT m1-11-2-nonclinical-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-2-nonclinical-information-amendment
ID ID #IMPLIED
>
<!ELEMENT m1-11-3-clinical-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-3-clinical-information-amendment
ID ID #IMPLIED
>
<!ELEMENT m1-11-4-multiple-module-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-4-multiple-module-information-amendment
ID ID #IMPLIED
>
<!ELEMENT m1-12-other-correspondence (m1-12-1-pre-ind-correspondence*, m1-12-2-
request-to-charge-for-clinical-trial*, m1-12-3-request-to-charge-for-expanded-access*, m1-12-4-
request-for-comments-and-advice*, m1-12-5-request-for-a-waiver*, m1-12-6-exception-from-
informed-consent-for-emergency-research*, m1-12-7-public-disclosure-statement-for-exception-
from-informed-consent-for-emergency-research*, m1-12-8-correspondence-regarding-exception-
from-informed-consent-for-emergency-research*, m1-12-9-notification-of-discontinuation-of-
clinical-trial*, m1-12-10-generic-drug-enforcement-act-statement*, m1-12-11-anda-basis-for-
submission-statement*, m1-12-12-comparison-of-generic-drug-and-reference-listed-drug*, m1-
12-13-request-for-waiver-for-in-vivo-studies*, m1-12-14-environmental-analysis*, m1-12-15-
request-for-waiver-of-in-vivo-bioavailability-studies*, m1-12-16-field-alert-reports*, m1-12-17-
orphan-drug-designation*)>
<!ATTLIST m1-12-other-correspondence
ID ID #IMPLIED
>
<!ELEMENT m1-12-1-pre-ind-correspondence ((leaf | node-extension)*)>
<!ATTLIST m1-12-1-pre-ind-correspondence
ID ID #IMPLIED
>
<!ELEMENT m1-12-2-request-to-charge-for-clinical-trial ((leaf | node-extension)*)>
<!ATTLIST m1-12-2-request-to-charge-for-clinical-trial
ID ID #IMPLIED
>
<!ELEMENT m1-12-3-request-to-charge-for-expanded-access ((leaf | node-extension)*)>
<!ATTLIST m1-12-3-request-to-charge-for-expanded-access
ID ID #IMPLIED
Version 2.3 30
>
<!ELEMENT m1-12-4-request-for-comments-and-advice ((leaf | node-extension)*)>
<!ATTLIST m1-12-4-request-for-comments-and-advice
ID ID #IMPLIED
>
<!ELEMENT m1-12-5-request-for-a-waiver ((leaf | node-extension)*)>
<!ATTLIST m1-12-5-request-for-a-waiver
ID ID #IMPLIED
>
<!ELEMENT m1-12-6-exception-from-informed-consent-for-emergency-research ((leaf | node-
extension)*)>
<!ATTLIST m1-12-6-exception-from-informed-consent-for-emergency-research
ID ID #IMPLIED
>
<!ELEMENT m1-12-7-public-disclosure-statement-for-exception-from-informed-consent-for-
emergency-research ((leaf | node-extension)*)>
<!ATTLIST m1-12-7-public-disclosure-statement-for-exception-from-informed-consent-for-
emergency-research
ID ID #IMPLIED
>
<!ELEMENT m1-12-8-correspondence-regarding-exception-from-informed-consent-for-
emergency-research ((leaf | node-extension)*)>
<!ATTLIST m1-12-8-correspondence-regarding-exception-from-informed-consent-for-
emergency-research
ID ID #IMPLIED
>
<!ELEMENT m1-12-9-notification-of-discontinuation-of-clinical-trial ((leaf | node-
extension)*)>
<!ATTLIST m1-12-9-notification-of-discontinuation-of-clinical-trial
ID ID #IMPLIED
>
<!ELEMENT m1-12-10-generic-drug-enforcement-act-statement ((leaf | node-extension)*)>
<!ATTLIST m1-12-10-generic-drug-enforcement-act-statement
ID ID #IMPLIED
>
<!ELEMENT m1-12-11-anda-basis-for-submission-statement ((leaf | node-extension)*)>
<!ATTLIST m1-12-11-anda-basis-for-submission-statement
ID ID #IMPLIED
Version 2.3 31
>
<!ELEMENT m1-12-12-comparison-of-generic-drug-and-reference-listed-drug ((leaf | node-
extension)*)>
<!ATTLIST m1-12-12-comparison-of-generic-drug-and-reference-listed-drug
ID ID #IMPLIED
>
<!ELEMENT m1-12-13-request-for-waiver-for-in-vivo-studies ((leaf | node-extension)*)>
<!ATTLIST m1-12-13-request-for-waiver-for-in-vivo-studies
ID ID #IMPLIED
>
<!ELEMENT m1-12-14-environmental-analysis ((leaf | node-extension)*)>
<!ATTLIST m1-12-14-environmental-analysis
ID ID #IMPLIED
>
<!ELEMENT m1-12-15-request-for-waiver-of-in-vivo-bioavailability-studies ((leaf | node-
extension)*)>
<!ATTLIST m1-12-15-request-for-waiver-of-in-vivo-bioavailability-studies
ID ID #IMPLIED
>
<!ELEMENT m1-12-16-field-alert-reports ((leaf | node-extension)*)>
<!ATTLIST m1-12-16-field-alert-reports
ID ID #IMPLIED
>
<!ELEMENT m1-12-17-orphan-drug-designation ((leaf | node-extension)*)>
<!ATTLIST m1-12-17-orphan-drug-designation
ID ID #IMPLIED
>
<!ELEMENT m1-13-annual-report (m1-13-1-summary-for-nonclinical-studies*, m1-13-2-
summary-of-clinical-pharmacology-information*, m1-13-3-summary-of-safety-information*,
m1-13-4-summary-of-labeling-changes*, m1-13-5-summary-of-manufacturing-changes*, m1-
13-6-summary-of-microbiological-changes*, m1-13-7-summary-of-other-significant-new-
information*, m1-13-8-individual-study-information*, m1-13-9-general-investigational-plan*,
m1-13-10-foreign-marketing*, m1-13-11-distribution-data*, m1-13-12-status-of-postmarketing-
study-commitments-and-requirements*, m1-13-13-status-of-other-postmarketing-studies-and-
requirements*, m1-13-14-log-of-outstanding-regulatory-business*, m1-13-15-development-
safety-update-report-dsur*)>
<!ATTLIST m1-13-annual-report
ID ID #IMPLIED
>
Version 2.3 32
<!ELEMENT m1-13-1-summary-for-nonclinical-studies ((leaf | node-extension)*)>

<!ATTLIST m1-13-1-summary-for-nonclinical-studies
ID ID #IMPLIED
>
<!ELEMENT m1-13-2-summary-of-clinical-pharmacology-information ((leaf | node-
extension)*)>
<!ATTLIST m1-13-2-summary-of-clinical-pharmacology-information
ID ID #IMPLIED
>
<!ELEMENT m1-13-3-summary-of-safety-information ((leaf | node-extension)*)>
<!ATTLIST m1-13-3-summary-of-safety-information
ID ID #IMPLIED
>
<!ELEMENT m1-13-4-summary-of-labeling-changes ((leaf | node-extension)*)>
<!ATTLIST m1-13-4-summary-of-labeling-changes
ID ID #IMPLIED
>
<!ELEMENT m1-13-5-summary-of-manufacturing-changes ((leaf | node-extension)*)>
<!ATTLIST m1-13-5-summary-of-manufacturing-changes
ID ID #IMPLIED
>
<!ELEMENT m1-13-6-summary-of-microbiological-changes ((leaf | node-extension)*)>
<!ATTLIST m1-13-6-summary-of-microbiological-changes
ID ID #IMPLIED
>
<!ELEMENT m1-13-7-summary-of-other-significant-new-information ((leaf | node-
extension)*)>
<!ATTLIST m1-13-7-summary-of-other-significant-new-information
ID ID #IMPLIED
>
<!ELEMENT m1-13-8-individual-study-information ((leaf | node-extension)*)>
<!ATTLIST m1-13-8-individual-study-information
ID ID #IMPLIED
>
<!ELEMENT m1-13-9-general-investigational-plan ((leaf | node-extension)*)>
<!ATTLIST m1-13-9-general-investigational-plan
ID ID #IMPLIED
Version 2.3 33
>
<!ELEMENT m1-13-10-foreign-marketing ((leaf | node-extension)*)>
<!ATTLIST m1-13-10-foreign-marketing
ID ID #IMPLIED
>
<!ELEMENT m1-13-11-distribution-data ((leaf | node-extension)*)>
<!ATTLIST m1-13-11-distribution-data
ID ID #IMPLIED
>
<!ELEMENT m1-13-12-status-of-postmarketing-study-commitments-and-requirements ((leaf |
node-extension)*)>
<!ELEMENT m1-13-13-status-of-other-postmarketing-studies-and-requirements ((leaf | node-
extension)*)>
<!ATTLIST m1-13-13-status-of-other-postmarketing-studies-and-requirements
ID ID #IMPLIED
>
<!ELEMENT m1-13-14-log-of-outstanding-regulatory-business ((leaf | node-extension)*)>
<!ATTLIST m1-13-14-log-of-outstanding-regulatory-business
ID ID #IMPLIED
>
<!ELEMENT m1-13-15-development-safety-update-report-dsur ((leaf | node-extension)*)>
<!ATTLIST m1-13-15-development-safety-update-report-dsur
ID ID #IMPLIED
>
<!ELEMENT m1-14-labeling (m1-14-1-draft-labeling*, m1-14-2-final-labeling*, m1-14-3-
listed-drug-labeling*, m1-14-4-investigational-drug-labeling*, m1-14-5-foreign-labeling*, m1-
14-6-product-labeling-for-2253-submissions*)>
<!ATTLIST m1-14-labeling
ID ID #IMPLIED
>
<!ELEMENT m1-14-1-draft-labeling (m1-14-1-1-draft-carton-and-container-labels*, m1-14-1-
2-annotated-draft-labeling-text*, m1-14-1-3-draft-labeling-text*, m1-14-1-4-label-
comprehension-studies*, m1-14-1-5-labeling-history*)>
<!ATTLIST m1-14-1-draft-labeling
ID ID #IMPLIED
>
<!ELEMENT m1-14-1-1-draft-carton-and-container-labels ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-1-draft-carton-and-container-labels
ID ID #IMPLIED
Version 2.3 34

>
<!ELEMENT m1-14-1-2-annotated-draft-labeling-text ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-2-annotated-draft-labeling-text
ID ID #IMPLIED
>
<!ELEMENT m1-14-1-3-draft-labeling-text ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-3-draft-labeling-text
ID ID #IMPLIED
>
<!ELEMENT m1-14-1-4-label-comprehension-studies ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-4-label-comprehension-studies
ID ID #IMPLIED
>
<!ELEMENT m1-14-1-5-labeling-history ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-5-labeling-history
ID ID #IMPLIED
>
<!ELEMENT m1-14-2-final-labeling (m1-14-2-1-final-carton-or-container-labels*, m1-14-2-2-
final-package-insert-package-inserts-patient-information-medication-guides*, m1-14-2-3-final-
labeling-text*)>
<!ATTLIST m1-14-2-final-labeling
ID ID #IMPLIED
>
<!ELEMENT m1-14-2-1-final-carton-or-container-labels ((leaf | node-extension)*)>
<!ATTLIST m1-14-2-1-final-carton-or-container-labels
ID ID #IMPLIED
>
<!ELEMENT m1-14-2-2-final-package-insert-package-inserts-patient-information-medication-
guides ((leaf | node-extension)*)>
<!ATTLIST m1-14-2-2-final-package-insert-package-inserts-patient-information-medication-
guides
ID ID #IMPLIED
>
<!ELEMENT m1-14-2-3-final-labeling-text ((leaf | node-extension)*)>
<!ATTLIST m1-14-2-3-final-labeling-text
ID ID #IMPLIED
>
Version 2.3 35
<!ELEMENT m1-14-3-listed-drug-labeling (m1-14-3-1-annotated-comparison-with-listed-

drug*, m1-14-3-2-approved-labeling-text-for-listed-drug*, m1-14-3-3-labeling-text-for-
reference-listed-drug*)>
<!ATTLIST m1-14-3-listed-drug-labeling
ID ID #IMPLIED
>
<!ELEMENT m1-14-3-1-annotated-comparison-with-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-14-3-1-annotated-comparison-with-listed-drug
ID ID #IMPLIED
>
<!ELEMENT m1-14-3-2-approved-labeling-text-for-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-14-3-2-approved-labeling-text-for-listed-drug
ID ID #IMPLIED
>
<!ELEMENT m1-14-3-3-labeling-text-for-reference-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-14-3-3-labeling-text-for-reference-listed-drug
ID ID #IMPLIED
>
<!ELEMENT m1-14-4-investigational-drug-labeling (m1-14-4-1-investigational-brochure*, m1-
14-4-2-investigational-drug-labeling*)>
<!ATTLIST m1-14-4-investigational-drug-labeling
ID ID #IMPLIED
>
<!ELEMENT m1-14-4-1-investigational-brochure ((leaf | node-extension)*)>
<!ATTLIST m1-14-4-1-investigational-brochure
ID ID #IMPLIED
>
<!ELEMENT m1-14-4-2-investigational-drug-labeling ((leaf | node-extension)*)>
<!ATTLIST m1-14-4-2-investigational-drug-labeling
ID ID #IMPLIED
>
<!ELEMENT m1-14-5-foreign-labeling ((leaf | node-extension)*)>
<!ATTLIST m1-14-5-foreign-labeling
ID ID #IMPLIED
>
<!ELEMENT m1-14-6-product-labeling-for-2253-submissions ((leaf | node-extension)*)>
<!ATTLIST m1-14-6-product-labeling-for-2253-submissions
ID ID #IMPLIED
Version 2.3 36

>
<!ELEMENT m1-15-promotional-material (m1-15-1-correspondence-relating-to-promotional-
materials?, m1-15-2-materials?)>
<!ATTLIST m1-15-promotional-material
ID ID #IMPLIED
promotional-material-audience-type CDATA #REQUIRED
>
<!ELEMENT m1-15-1-correspondence-relating-to-promotional-materials (m1-15-1-1-request-
for-advisory-comments-on-launch-materials?, m1-15-1-2-request-for-advisory-comments-on-
non-launch-materials?, m1-15-1-3-pre-submission-of-launch-promotional-materials-for-
accelerated-approval-products?, m1-15-1-4-pre-submission-of-non-launch-promotional-
materials-for-accelerated-approval-products?, m1-15-1-5-pre-dissemination-review-of-
television-ads?, m1-15-1-6-response-to-untitled-letter-or-warning-letter?, m1-15-1-7-response-
to-information-request?, m1-15-1-8-correspondence-accompanying-materials-previously-
missing-or-rejected?, m1-15-1-9-withdrawal-request?, m1-15-1-10-submission-of-annotated-
references?, m1-15-1-11-general-correspondence?)>
<!ATTLIST m1-15-1-correspondence-relating-to-promotional-materials
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-1-request-for-advisory-comments-on-launch-materials ((leaf | node-
extension)*)>
<!ATTLIST m1-15-1-1-request-for-advisory-comments-on-launch-materials
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-2-request-for-advisory-comments-on-non-launch-materials ((leaf | node-
extension)*)>
<!ATTLIST m1-15-1-2-request-for-advisory-comments-on-non-launch-materials
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-3-pre-submission-of-launch-promotional-materials-for-accelerated-
approval-products ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-3-pre-submission-of-launch-promotional-materials-for-accelerated-
approval-products
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-4-pre-submission-of-non-launch-promotional-materials-for-accelerated-
approval-products ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-4-pre-submission-of-non-launch-promotional-materials-for-accelerated-
approval-products
ID ID #IMPLIED
Version 2.3 37

>
<!ELEMENT m1-15-1-5-pre-dissemination-review-of-television-ads ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-5-pre-dissemination-review-of-television-ads
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-6-response-to-untitled-letter-or-warning-letter ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-6-response-to-untitled-letter-or-warning-letter
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-7-response-to-information-request ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-7-response-to-information-request
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-8-correspondence-accompanying-materials-previously-missing-or-
rejected ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-8-correspondence-accompanying-materials-previously-missing-or-rejected
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-9-withdrawal-request ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-9-withdrawal-request
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-10-submission-of-annotated-references ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-10-submission-of-annotated-references
ID ID #IMPLIED
>
<!ELEMENT m1-15-1-11-general-correspondence ((leaf | node-extension)*)>
<!ATTLIST m1-15-1-11-general-correspondence
ID ID #IMPLIED
>
<!ELEMENT m1-15-2-materials (m1-15-2-1-material*)>
<!ATTLIST m1-15-2-materials
ID ID #IMPLIED
promotional-material-doc-type CDATA #REQUIRED
>
<!ELEMENT m1-15-2-1-material (m1-15-2-1-1-clean-version?, m1-15-2-1-2-annotated-
version?, m1-15-2-1-3-annotated-labeling-version?, m1-15-2-1-4-annotated-references?)>
Version 2.3 38
<!ATTLIST m1-15-2-1-material
ID ID #IMPLIED
promotional-material-type CDATA #REQUIRED
material-id CDATA #REQUIRED
issue-date CDATA #IMPLIED
>
<!ELEMENT m1-15-2-1-1-clean-version ((leaf | node-extension)*)>
<!ATTLIST m1-15-2-1-1-clean-version
ID ID #IMPLIED
>
<!ELEMENT m1-15-2-1-2-annotated-version ((leaf | node-extension)*)>
<!ATTLIST m1-15-2-1-2-annotated-version
ID ID #IMPLIED
>
<!ELEMENT m1-15-2-1-3-annotated-labeling-version ((leaf | node-extension)*)>
<!ATTLIST m1-15-2-1-3-annotated-labeling-version
ID ID #IMPLIED
>
<!ELEMENT m1-15-2-1-4-annotated-references ((leaf | node-extension)*)>
<!ATTLIST m1-15-2-1-4-annotated-references
ID ID #IMPLIED
>
<!ELEMENT m1-16-risk-management-plan (m1-16-1-risk-management-non-rems?, m1-16-2-
risk-evaluation-and-mitigation-strategies-rems?)>
<!ATTLIST m1-16-risk-management-plan
ID ID #IMPLIED
>
<!ELEMENT m1-16-1-risk-management-non-rems ((leaf | node-extension)*)>
<!ATTLIST m1-16-1-risk-management-non-rems
ID ID #IMPLIED
>
<!ELEMENT m1-16-2-risk-evaluation-and-mitigation-strategies-rems (m1-16-2-1-final-rems?,
m1-16-2-2-draft-rems?, m1-16-2-3-rems-assessment?, m1-16-2-4-rems-assessment-
methodology?, m1-16-2-5-rems-correspondence?, m1-16-2-6-rems-modification-history?)>
<!ATTLIST m1-16-2-risk-evaluation-and-mitigation-strategies-rems
ID ID #IMPLIED
>
<!ELEMENT m1-16-2-1-final-rems ((leaf | node-extension)*)>
Version 2.3 39
<!ATTLIST m1-16-2-1-final-rems
ID ID #IMPLIED
>
<!ELEMENT m1-16-2-2-draft-rems ((leaf | node-extension)*)>
<!ATTLIST m1-16-2-2-draft-rems
ID ID #IMPLIED
>
<!ELEMENT m1-16-2-3-rems-assessment ((leaf | node-extension)*)>
<!ATTLIST m1-16-2-3-rems-assessment
ID ID #IMPLIED
>
<!ELEMENT m1-16-2-4-rems-assessment-methodology ((leaf | node-extension)*)>
<!ATTLIST m1-16-2-4-rems-assessment-methodology
ID ID #IMPLIED
>
<!ELEMENT m1-16-2-5-rems-correspondence ((leaf | node-extension)*)>
<!ATTLIST m1-16-2-5-rems-correspondence
ID ID #IMPLIED
>
<!ELEMENT m1-16-2-6-rems-modification-history ((leaf | node-extension)*)>
<!ATTLIST m1-16-2-6-rems-modification-history
ID ID #IMPLIED
>
<!ELEMENT m1-17-postmarketing-studies (m1-17-1-correspondence-regarding-postmarketing-
commitments*, m1-17-2-correspondence-regarding-postmarketing-requirements*)>
<!ATTLIST m1-17-postmarketing-studies
ID ID #IMPLIED
>
<!ELEMENT m1-17-1-correspondence-regarding-postmarketing-commitments ((leaf | node-
extension)*)>
<!ATTLIST m1-17-1-correspondence-regarding-postmarketing-commitments
ID ID #IMPLIED
>
<!ELEMENT m1-17-2-correspondence-regarding-postmarketing-requirements ((leaf | node-
extension)*)>
<!ATTLIST m1-17-2-correspondence-regarding-postmarketing-requirements
ID ID #IMPLIED
Version 2.3 40
>
<!ELEMENT m1-18-proprietary-names ((leaf | node-extension)*)>
<!ATTLIST m1-18-proprietary-names
ID ID #IMPLIED
>
<!ELEMENT m1-19-pre-eua-and-eua ((leaf | node-extension)*)>
<!ATTLIST m1-19-pre-eua-and-eua
ID ID #IMPLIED
>
<!ELEMENT m1-20-general-investigational-plan-for-initial-ind ((leaf | node-extension)*)>
<!ATTLIST m1-20-general-investigational-plan-for-initial-ind
ID ID #IMPLIED
>
Version 2.3 41
APPENDIX 2: Summary of Changes for Versions of The eCTD

Backbone Files Specification for Module 1
A. Summary of Changes for Version 2.3

1. References to 503B were modified and/or replaced with Pre-dissemination review
of television ads due to re-designation of 503B to 503C (21 USC 353c). The
updated sections are listed below:
a. The description of ‘Resubmission’ in Table 4 (Submission Sub-Types and
Descriptions of Use).
b. The promotional material doc type and its description in Table 12
(Promotional Material Doc Types and Descriptions).
2. Changed DTD version references from 3.2 to 3.3 where applicable and replaced the
copy of DTD Version 3.2 in Appendix I with DTD Version 3.3.
B. Summary of Changes for Version 2.2

3. Changed DTD version references from 3.1 to 3.2 where applicable and replaced the
copy of DTD Version 3.1 in Appendix I with DTD Version 3.2.
4. Revised text, revised table 1, and added table 13 to indicate the new required attribute
material-id and the new optional attribute issue-date which applies to m1-15-2-1.
C. Summary of Changes for Version 2.1

1. Changed DTD version references from 3.0 to 3.1 and replaced the copy of DTD
Version 3.0 in Appendix I with DTD Version 3.1.
a. Version 3.1 of the DTD includes changes to the m1-16 heading and m1-16 sub-
headings were added.
D. Summary of Changes for Version 2.0

The following is a brief summary of the changes incorporated in version 2.0 of the Module 1
Backbone Files Specification. Please refer to specific sections within this document to obtain a more
detailed description of the changes. The changes made are consistent with eCTD v4, to be
implemented using the Regulated Product Submission (RPS) exchange standard.
1. The date-of-submission and product-information elements were removed.

2. Module 1 heading 1.9.5 “Proposal for written agreement” was removed. If leaves were
previously referenced under a heading element that was removed, lifecycle operators
can still be used to delete the leaves. No “new” or “replaced” leaves should be
referenced under removed heading elements.
3. An id element was added under applicant-info to provide the applicant’s or
sponsor’s corporate DUNS number issued by Dunn & Bradstreet to supplement
other identifiers such as the company-name element.
Version 2.3 42
4. The submission-description element was added and is optional. The element is limited
to 128 characters. It allows for an additional brief description of the purpose of the
submission, but should not contain any reviewable information.
5. The applicant-contacts element was added to capture contact information. One or more
contact names, telephone numbers, and email addresses may be submitted for each
submission, and at least one contact name is required.
6. The application-set element can contain one or many applications (i.e., grouped
submission). Each application needs to have its own submission information section.
When a grouped submission is submitted, the submission content will reside under a
single application, but is referenced by multiple eCTD applications. The application-
contains-files element was added to indicate which application contains the files in a
grouped submission. This attribute will be used to identify the root application where
the submission files will be stored.
7. The element cross-reference-application-number was added to provide the ability to
list cross-referenced applications. An example is an ANDA referencing a DMF; the
ANDA submission would reference the application type (DMF) and application number
(DMF number) in the cross-reference-application-number element.
8. A new submission-information element has been introduced to group information
about the submission. The submission-information element contains three elements
(submission-id, sequence-number, and form).
9. Certain forms are provided under the submission-information element to allow each
application’s form to be displayed within the appropriate application.
10. Submission type was changed from an element to be an attribute of the submission-id
element. In addition, an attribute of supplement-effective-date-type was added and is
also an attribute of the submission-id element. The supplement-effective-date-type is
only applicable if the submission-type is an efficacy, labeling or CMC supplement and
the submission-sub-type is “application.”
11. The sequence-number element was relocated under the submission-information
element to group similar elements with information about the submission.
12. An attribute for submission-sub-type was added to more accurately reflect the nature of
a submission and its relationship to the associated regulatory activity.
13. Submissions are grouped with their regulatory activity by using the submission-type,
submission-id, and sequence-number.
Example #1: The Original Application regulatory activity below has two presubmissions, the
original application submission, and two amendments.
New Module 1 Old Module 1
Presubmission (meeting request)
application-containing files true
submission-id 0001
submission-type attribute fdast1 (Original Application) Sequence: 0000
sequence-number 0001 Related Sequence: Null
Presubmission (meeting briefing
Version 2.3 43
package)
submission-id 0001
Original Application
submission-id 0001
Amendment #1
submission-id 0001
sequence-number 0004 Related Sequence: 0002
Amendment #2
submission-id 0001
sequence-number 0005 Related Sequence: 0002
Example #2: The Efficacy Supplement regulatory activity below has the supplement submission
and two amendments.
New Module 1 Old Module 1
Efficacy Supplement (new indication)
submission-id 0006
supplement-effective-date-type attribute fdasedt1 (Prior Approval
Supplement (PAS))
sequence-number 0006 Sequence: 0006
submission-sub-type attribute fdasst3 (application) Related Sequence: Null
Amendment #1 to Efficacy
Supplement
submission-id 0006
submission-sub-type attribute fdasst3 (amendment) Related Sequence: 0006
Amendment #2 to Efficacy
Supplement
submission-id 0006
Version 2.3 44
submission-sub-type attribute fdasst3 (amendment) Related Sequence: 0006
14. Certain admin and module 1 elements (m1-1-forms and the sections and subsections of
m1-15-promotional-material) require an attribute.
15. Additional headings elements were added to 1.15 Promotional material to further
define the submission of promotional materials.
16. Additional heading elements were added or revised. Please refer to the The
Comprehensive Table of Contents Headings and Hierarchy for the complete set of
changes.
17. The us-regional.xml refers to and validates from supporting and required files (DTD,
stylesheet, and value-type lists) located at web site addresses instead of local file paths
(previously required files were located in the util folder). The stylesheet (us-
regional.xsl) was updated to refer to the new attribute value lists (XML files) and DTD
for the purpose of validation and display.
18. The heading table was removed from the Heading Elements for Module 1 section.
Version 2.3 45
Specifications for File Format Types Using eCTD Specifications
Revision History
2013-04-11 1.0 Initial version
1
This document provides specifications for submitting file format types using eCTD
specifications. A list of accepted file types, and the eCTD locations in which those file
types are permissible are provided. The file types in the tables below may be provided only
in the specific sections listed.
I. General Information
Documents should be provided in PDF searchable format. Images (e.g., BMP, JPG, GIF,
PNG) should be rendered into PDF format and retain searchable text whenever possible.
When this isn’t possible, please refer to the tables below. Additional information related to
PDF documents is available in the FDA technical specification FDA Portable Document
Format (PDF) Specifications.
II. Acceptable File Formats for Use in eCTD Module 1

Documents Format Name/Description Accepted in eCTD
and Modules/Headings
Labeling
DOC Microsoft Word document m1-14 sub-sections
DOCX Office Open XML document m1-14 sub-sections
XML Extensible Markup Language m1\us\[labeling\spl]
GIF Graphic Interchange Format (CompuServe m1-14 and m1-15 sub-sections
Bitmap)
JPG, JPEG JPEG Image File m1-14 and m1-15 sub-sections
PNG Portable Network Graphics Bitmap m1-14 and m1-15 sub-sections
Audio Format Name/Description Accepted in eCTD

format Modules/Headings
AU Music File (various, usually Sun or UNIX) m1-15 sub-sections
MP2 MPEG Audio Stream, Layer II (MIME video m1-15 sub-sections
file)
MP3 MPEG Audio Stream, Layer III m1-15 sub-sections
MP4 MPEG-4 Video File m1-15 sub-sections
WAV Windows Waveform Sound m1-15 sub-sections
WMA Windows Media File (contains audio) m1-15 sub-sections
Video Format Name/Description Accepted in eCTD

AVI Audio Video Interleave File m1-15 sub-sections
FLV Flash Video m1-15 sub-sections
MPEG Moving Picture Experts Group (MPEG m1-15 sub-sections
Movie)
SWF Macromedia Flash (for viewing) m1-15 sub-sections
2
Video Format Name/Description Accepted in eCTD

WMV Windows Media File (contains both video m1-15 sub-sections
and audio)
Images Format Name/Description Accepted in eCTD

Modules/Headings
BMP Windows or OS/2 Bitmap Graphics m1-15 sub-sections
GIF Graphic Interchange Format (CompuServe m1-15 sub-sections
Bitmap)
JPG, JPEG JPEG Image File m1-15 sub-sections
PNG Portable Network Graphics Bitmap m1-15 sub-sections
Web Format Name/Description Accepted in eCTD

HTM, HyperText Markup Language m1-15 sub-sections
HTML
Flash and Macromedia Flash Source File m1-15 sub-sections
Shockwave
(.f4v, .fla, Macromedia Shockwave Flash Format
.flv, .swf)
III. eCTD Modules 2 through 5

File Types Format Name/Description eCTD Module/Section
CSS Cascading Style Sheets m4, m5 (CDISC metadata)
DAT Data File m4, m5 (data)
GIF CompuServe's Graphics Interchange Format m2 – m5
JPG Joint Photographic Group m2 – m5
PNG Portable Network Graphics Bitmap m2 – m5
SVG Scalable Vector Graphics m2 – m5
TXT Text Document File m3 - m5 (data)
XML Extensible Markup Language m4, m5 (CDISC metadata)
XPT SAS Transport File m3 - m5 (data)
XSD XML Schema m4, m5 (CDISC metadata)
XSL Extensible Stylesheet Language (XML m4, m5 (CDISC metadata)
Stylesheet)
3
IV. Supportive Required File Formats
eCTD Format Name/Description eCTD Folder Location or

Supportive Module/Section Referencing File
Required Formats
DTD Data Type Definition [sequence number folder]\util\dtd
folder
XSL Extensible Stylesheet Language (XML [sequence number folder]\util\style
Stylesheet) folder
XML Extensible Markup Language [sequence number folder], m1, m5
References:
References are available on the eCTD Web Page:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/E
lectronicSubmissions/ucm153574.htm.
ICH M2 EWG technical specification, Electronic Common Technical Document

Specification
FDA Guidance for Industry, Providing Regulatory Submissions in Electronic

Format — Human Pharmaceutical Product Applications and Related Submissions
Using the eCTD Specifications
Portable Document Format (PDF) Specifications
Study Data Specifications
eCTD Backbone Files Specification for Module 1 (versions 1.3 and 2.1)
eCTD Backbone File Specification for Modules 2 through 5 3.2.2
The eCTD Backbone File Specification for Study Tagging Files 2.6.1
Questions may be sent to:
CDER: [email protected]
CBER: [email protected]
Data-related questions: [email protected]
4
Specification for Transmitting Electronic Submissions using eCTD Specifications
Revision History
2005-06-14 1.1 Correction of typographical error in Type of Media table
2009-08-27 1.2 Removal of Media Type Floppy Disk
Updated LTO specifications
Added information regarding ESG
2010-08-02 1.3 Change to Address for electronic submission sent on physical
media
CDER Office of Generic Drugs address change
2011-12-28 1.4 Added information regarding USB media format
Added retirement date for Tape options
Added email address for Questions/Communication with Centers
2012-07-26 1.5 Clarification that USB encryption is optional
Rewording information regarding password protection of data vs.
USB drive
1
Specification for Transmitting Electronic Submissions using eCTD

Specifications
This document provides specification for transmitting electronic submissions using eCTD
specifications. Details are included for transmitting the electronic submission on physical media
or electronically.
I. ELECTRONIC TRANSMISSION
FDA prefers to receive submissions via the Electronic Secure Gateway (ESG) rather than on
physical media. Whenever possible, please use the ESG. See
http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm
for more information.
II. PHYSICAL MEDIA
A. Address for electronic submissions sent on physical media
CBER:
U.S. Food and Drug Administration

Center for Biologics Evaluation and Research
Document Control Center
1401 Rockville Pike, HFM-99
Rockville, MD 20832-1448
CDER:
U.S. Food and Drug Administration

Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
U. S. Food and Drug Administration

Office of Generic Drugs – HFD-600
Center for Drug Evaluation and Research
Metro Park North II
7500 Standish Place, Rm. 150
Rockville, MD 20855-2773
2
B. Types of physical media accepted
See the following table:
Type of media Format Size

CD ROM CD-R Joliet Specification Up to 3 GB (1- 5 CDs)
DVD DVD-R Up to 45 GB (1 to 6 DVDs)
DVD+R
DVD+/-R
Digital Linear Tape 35/70 or 40/80 DLT tapes using No limit
DLT-IV* BackupExec, or (contact Agency Center for any
Windows 2000/2003 native backup submission over 45 GB)
Linear Tape Open LTO 1, 2, 3, or 4 tapes using No limit
LTO* BackupExec, or (contact Agency for any submission
Windows 2000/2003 native backup over 45 GB)
USB drive  Device Type: External hard drive Over 45 GB only
Size not to exceed: (contact the Agency Center in
Width: 4 in advance for specific instructions on
Depth: 5 in how to send – see below for email
Height: 1 in addresses)
 Interface: Hi-Speed USB 2.0
with a Type A connector IMPORTANT:
 Passcode: use 6 to 24 digits DO NOT SUBMIT USB DRIVES
(optional) FOR SUBMISSIONS UNDER 45
 Compliant Standards: 128-bit GB
AES (Advanced Encryption
Standard)
 Driverless operation
 Built-in USB cable with included
power source: USB Bus
*THESE TAPE FORMATS WILL BE RETIRED ON 12/31/2012
IMPORTANT: Do not compress data. Do not password protect any data. The only
exception is the optional passcode encryption of a USB drive.
3
C. Media preparation
Send all electronic media adequately secured in a standard binder marked clearly on the
outside ELECTRONIC REGULATORY SUBMISSION FOR ARCHIVE. Do not send
unlabeled media.
The following information should be included on the media labels:

Sponsor, applicant or company name
Name of the product, chemical or ingredient
Appropriate regulatory ID number (e.g., NDA application number)
Submission date (dd-mmm-yyyy)
Media series (e.g., “1 of 1”, “1 of 2”)
Questions may be sent to:

CDER: [email protected]
CBER: [email protected]
4
ICH eCTD Specification V 3.2.2 16-July-2008
INTERNATIONAL CONFERENCE ON HARMONISATION OF

TECHNICAL REQUIREMENTS FOR REGISTRATION OF
PHARMACEUTICALS FOR HUMAN USE
ICH M2 EWG
Electronic Common Technical Document Specification
This specification has been developed by the ICH M2 Expert Working

Group and maintained by the eCTD Implementation Working Group in
accordance with the ICH Process as pertains to the M2 EWG and eCTD
change control as it pertains to the eCTD IWG.
Document Change History

Version Date Description
Number
Version 3.0 October 2003 Initial Step 4 Document
Version 3.1 November 2003 Incorporated approved change
requests 00020, 00030, 00090, 00110,
00190, 00200, 00240, 00260, 00290,
00310, 00380, 00400, 00420, 00450,
00480, 00500, 00510, 00520, 00530
Version 3.2 February 2004 Editorial Corrections and Changes to
Align with the M4 Organisation
Document : Granularity Annex
Version 3.2.1 June 2008 Incorporated approved change
requests 0120, 0130, 0140, 0210,
0270, 0300, 0390, 0560, 0590, 0600,
0620, 0640, 0670, 0700, 0710, 0720,
0730, 0750, 0760, 0770, 0780, 0810,
0820, 0940, 0960, 1030, 1080, 01170,
1250, 1280, 1310, 1320, 1360, 1370,
1400, 1450, 1580, 1660, 1680.
Incorporated eCTD Q&As 1-3, 5-7, 9-
11, 13, 15, 17-19, 21, 23, 24, 28-34,
37-39 and 41-47. Provided clarity on
Operation Attribute use. Converted all
instances of ‘leafs’ to ‘leaf elements’.
Removed numbering not defined by
CTD (e.g., 4.2.1.1.1). Introduced
allowance for ‘append’ leaf to modify
leaf in same sequence. Corrected typos
and other wording issues.
Version 3.2.2 July 2008 Minor editorial corrections after Step 4
approval and sign-off
ICH eCTD Specification................................................................................................................. 1

Introduction ................................................................................................................................. 1
Background.................................................................................................................................. 1
Scope ........................................................................................................................................... 1
Technical Requirements .............................................................................................................. 1
Change Control............................................................................................................................ 1
Appendix 1: Overall Architecture................................................................................................ 1-1
Guiding Design Principles........................................................................................................ 1-1
Business Model......................................................................................................................... 1-1
Modular Structure of the eCTD................................................................................................ 1-1
XML Based eCTD.................................................................................................................... 1-1
Multiple Region Support .......................................................................................................... 1-2
Life Cycle Management ........................................................................................................... 1-2
Appendix 2: The eCTD Submission ............................................................................................ 2-1
Introduction .............................................................................................................................. 2-1
The eCTD Submission.............................................................................................................. 2-1
Directory Structure............................................................................................................... 2-1
XML eCTD Instance ............................................................................................................ 2-1
eCTD Template ........................................................................................................................ 2-1
Formats ..................................................................................................................................... 2-1
Common Formats ..................................................................................................................... 2-2
Regional Use of Other Formats ................................................................................................ 2-2
Links ......................................................................................................................................... 2-2
Presentation .............................................................................................................................. 2-2
Checksums................................................................................................................................ 2-2
Element to File Directory Mapping.......................................................................................... 2-2
File Extension ........................................................................................................................... 2-3
Name......................................................................................................................................... 2-3
Character encoding ................................................................................................................... 2-4
References ................................................................................................................................ 2-4
Appendix 3: General Considerations for the CTD Modules ....................................................... 3-1
Introduction .............................................................................................................................. 3-1
Folder and File Naming Conventions....................................................................................... 3-1
Screenshots and Folder Hierarchy............................................................................................ 3-2
Module 1 Administrative Information and Prescribing Information........................................ 3-2
Module 2 Summaries................................................................................................................ 3-2
Module 3 Quality...................................................................................................................... 3-4
Module 4 Nonclinical Study Reports ....................................................................................... 3-7
Module 5 Clinical Study Reports ........................................................................................... 3-10
Appendix 4: File Organization for the eCTD .............................................................................. 4-1
Appendix 5: Region Specific Information Including Transmission and Receipt ........................ 5-1
Introduction .............................................................................................................................. 5-1
Region Specific Information: Module 1................................................................................... 5-1
Submission Addresses .............................................................................................................. 5-1
Media ........................................................................................................................................ 5-2
Cover Letter.............................................................................................................................. 5-2
Transport................................................................................................................................... 5-2
Security..................................................................................................................................... 5-2
Receipt ...................................................................................................................................... 5-3
Acknowledgment...................................................................................................................... 5-3
Appendix 6: The eCTD XML Submission .................................................................................. 6-1
Background............................................................................................................................... 6-1
File Names and Directory Structure ......................................................................................... 6-1
Life Cycle Management ........................................................................................................... 6-2
Operation Attribute................................................................................................................... 6-3
File Reuse ................................................................................................................................. 6-5
DTD Content Model................................................................................................................. 6-6
eCTD Element/Attribute Instructions....................................................................................... 6-8
Example 6-1: Instructions for a Simple New Submission...................................................... 6-11
Example 6-2: Instructions for an Amendment, Supplement, or Variation............................. 6-12
Example 6-3: Instructions for Multiple Indications ............................................................... 6-12
Example 6-4: Instructions for Multiple Drug Substances, Manufacturers, and Products ...... 6-13
Example 6-5: Instructions for Extending XML eCTD DTD Elements.................................. 6-15
Example 6-6: Instructions for Submitting Sections as Paper ................................................. 6-15
Appendix 7: Specification for Submission Formats .................................................................... 7-1
Introduction .............................................................................................................................. 7-1
PDF........................................................................................................................................... 7-1
Version .................................................................................................................................. 7-1
Fonts ..................................................................................................................................... 7-1
Definition of Subset.............................................................................................................. 7-1
Notes on Embedding Japanese Fonts: ................................................................................ 7-2
Font Size ............................................................................................................................... 7-2
Use of Color Fonts ............................................................................................................... 7-2
Page Orientation................................................................................................................... 7-2
Page Size and Margins......................................................................................................... 7-2
Headers and Footers ............................................................................................................ 7-2
Source of Electronic Document........................................................................................... 7-3
Methods for Creating PDF Documents and Images .......................................................... 7-3
Hypertext Linking and Bookmarks ..................................................................................... 7-3
Page Numbering................................................................................................................... 7-4
Document Information Fields ............................................................................................. 7-4
Open Dialog Box .................................................................................................................. 7-4
Security ................................................................................................................................. 7-4
Indexing PDF Documents ................................................................................................... 7-4
Use of Acrobat Plug-Ins....................................................................................................... 7-5
XML Files................................................................................................................................. 7-5
SVG Files ................................................................................................................................. 7-5
Appendix 8: XML eCTD DTD.................................................................................................... 8-1
ICH eCTD Specification

Introduction
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). 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 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.
Background
The specification for the eCTD is based upon content defined within the CTD issued by the ICH M4 EWG.
The CTD describes the organization of modules, sections and documents. The structure and level of detail
specified in the CTD have been used as the basis for defining the eCTD structure and content but, where
appropriate, additional details have been developed within the eCTD specification.
The philosophy of the eCTD is to use open standards. Open standards, including proprietary standards
which through their widespread use can be considered de facto standards, are deemed to be appropriate in
general.
Scope
The CTD as defined by the M4 EWG does not cover the full submission that is to be made in a region. It
describes only modules 2 to 5, which are common across all regions. The CTD does not describe the
content of module 1, the Regional Administrative Information and Prescribing Information, nor does it
describe documents that can be submitted as amendments or variations to the initial application.
The value of producing a specification for the creation of an electronic submission based only upon the
modules described in the CTD would be limited. Therefore, the M2 EWG has produced a specification for
the eCTD that is applicable to all modules of initial registration applications and for other submissions of
information throughout the life cycle of the product, such as variations and amendments.
This document describes the parts of the registration application that are common to all regions and some
of the life cycle requirements for products. The parts of the registration application that are specific to a
region will be covered by regional guidance. However, this backbone has been developed to handle both
the regional and common parts of submissions.
Technical Requirements
The specification is designed to support high-level functional requirements such as the following:
• Copy and paste

• Viewing and printing of documents
• Annotation of documentation
• Facilitate the exporting of information to databases
• Searching within and across applications
• Navigation throughout the eCTD and its subsequent amendments/variations
Change Control
The specification for the eCTD is likely to change with time. Factors that could affect the content of the
specification include, but are not limited to:
Page 1
• Change in the content of the CTD, either through the amendment of information, at the same level
of detail, or by provision of more detailed definition of content and structure
• Change to the regional requirements for applications that are outside the scope of the CTD
• Updating standards that are already in use within the eCTD
• Identification of new standards that provide additional value for the creation and/or usage of the
eCTD
• Identification of new functional requirements
• Experience of use of the eCTD by all parties
Details of the change control management are described in an external ICH document.
Page 2
Appendix 1: Overall Architecture
Guiding Design Principles

This appendix defines the basic principles that drove the design and architecture of the eCTD. Detailed
specifications are defined in appendices 2 and 6.
Business Model
The business process to be supported can be described as follow:
Industry <-----> Message <------> Agency
The business process defines specific requirements for the message. The eCTD Specification currently
provides only a transport mechanism for one-way traffic from applicant to agency.
The primary focus of the eCTD is to provide a data interchange message between industry and agencies.
Industry initiates the process by creating the initial submission in terms of an electronic CTD. Throughout
the life cycle of this process, additional information will be submitted to update or modify the information
contained in the initial submission (e.g., supplement, amendment, variation.) The agency can submit
acknowledgements, queries and requests to industry. These are considered simple messages using
electronic mail or other transport formats. The overall architecture of the eCTD is designed to provide a
commonly agreed upon submission and submission structure that imposes minimal restriction to the
industry and agencies.
Modular Structure of the eCTD

The structure of the electronic submission in terms of organization and navigation should be consistent with
the modular structure of the Common Technical Document. The goal of this design principle is to
standardize the electronic format of the common parts of the eCTD.
XML Based eCTD

The XML eCTD DTD (Document Type Definition) defines the overall structure of the submission. The
purpose of the XML backbone is two-fold: (1) to manage meta-data for the entire submission and each
document within the submission and (2) to constitute a comprehensive table of contents and provide
corresponding navigation aids. Meta-data on submission level include information about submitting and
receiving organization, manufacturer, publisher, ID and kind of the submission, and related data items.
Examples for meta-data on document level are versioning information, language, descriptive information
such as document names and checksums. Details are defined in appendix 6.
The XML instance of any submission should be created and validated according to the XML eCTD DTD as
defined in appendix 8.
The XML eCTD DTD describes the hierarchical structure according to the CTD as defined by the ICH M4
Expert Working Group. It includes multiple hierarchical levels depending on the specific module as
defined in the CTD. The actual submission can include more hierarchical levels below those defined in the
CTD. The XML eCTD instance covers the entire submission including all hierarchical levels and includes
references to each individual file.
The submission should include a Stylesheet that supports presentation of the XML instance, navigation
according to the table of contents, and provides access to all documents within the submission. A standard
Stylesheet for viewing the eCTD submission is defined and provided by the ICH M2 EWG. Presentation
and navigation via other Stylesheets on the receiving side should be possible. Consult regional authorities
on the acceptability of submitting non-ICH stylesheets.
Page 1-1
Multiple Region Support
The scope of each submission is global according to the Common Technical Document, meaning that
modules 2 through 5 of a submission are intended for all regions with the exception of selected documents
(e.g., in the quality module), which have a regional scope. Module 1 of a submission is regional in nature.
The DTD as defined by the ICH M2 expert working group specifies the structure of the common parts of
the eCTD primarily focusing on module 2 through 5. It enables linking to regional XML index files for
module 1 which will be defined by the authorities in each region. Due to the significant differences in
documentation requirements across regions it is not expected that a single, global eCTD submission could
be constructed and transmitted to multiple regions with each regional authority ignoring or deleting other
regions' submission material.
Life Cycle Management

The applicant creates a submission that is stored in a local repository. The applicant submits the initial
submission to the agency, which imports the submission into another local repository. The nature and kind
of the local repositories is not within the scope of the eCTD. The initial submission should be self-
contained, meaning that it includes all documents and no references to other submissions. Regional
guidance should be consulted if references to other submissions are needed.
Following the initial submission, the applicant can submit incremental updates such as amendments and
variations. Updates can refer to documents in the previous submissions. Updates should be designed in a
way that they can be loaded into the repository by fully preserving the initial or previous submission via
version control. The XML backbone should include meta-data identifying the update and providing
navigation aids to filter for different submission types.
It is preferred that when a Common Technical Document is submitted electronically, the entire submission
be in electronic form with the exception of certain regional forms that currently require written signatures.
See appendix 5 for regional requirements. See appendix 6 for a description of how to submit a CTD
containing both paper and electronic components.
Page 1-2
Appendix 2: The eCTD Submission
Introduction
This appendix specifies the Information Technology aspect of the eCTD submission. Informally, the eCTD
submission is a directory structure with files including the XML eCTD instance, reports, data and other
submission information. The eCTD submission supports multilingual and multi-region aspects.
The eCTD Submission

• An eCTD submission is a collection of data objects that follows the eCTD specification. The main
function of the eCTD submission is data exchange. Information systems would need to be developed to
process the eCTD submission. The biggest benefits are expected when the eCTD submission is loaded
into an information system that supports the review process. However, one can view an eCTD
submission with a Web browser as it is Web ready.
The eCTD submission is composed of the following:

• Directory structure
• XML eCTD instance
• Content files
Directory Structure
The directory structure is a structure of directories and files. There should be a reasonable maximum
number of entries (directories and files) per directory. The directory structure should follow the rules
below. The files could be in several formats as specified below.
The name of the files and directories are identifiers. They should be short. The file names are not intended
to convey meta-data, though some meaning in the names helps (i.e., no random names.)
Recommended, but optional, names for directories and files are provided in Appendix 4. Any directory
names and file names that are added to the eCTD submission by the applicant should be descriptive, logical
and brief.
XML eCTD Instance

The instance is in the submission sequence number directory (see appendix 6). The submission sequence
number directory should contain at least two files and one or more directories. One of the files in the
submission sequence directory should be the instance and the other should be the MD5 checksum of the
instance. The instance is the starting file for the processing by an XML processor.
The intention is to have links from the leaf elements of the instance to the files in the eCTD submission as
opposed to creating a single XML document that contains the entire eCTD submission. The instance also
contains meta-data at the leaf level.
eCTD Template
The ICH Web site (http://estri.ich.org/eCTD) includes an empty eCTD folder template as an example of an
eCTD submission folder structure. It shows all of the possible Module 2-5 folders as defined in Appendix 4
and can be populated with the applicant data and edited as appropriate (i.e., adding additional subfolders or
removing unnecessary folders). The applicant should still add the relevant regional Module 1 folders and
content, add the appropriate utility folders and content, and create the XML index files to complete a valid
eCTD submission.
Formats
Formats should be readable at least for as long as it is needed for the regulatory process. This process could
be very long (e.g., 50 years). This points to the advantage of neutral formats: formal standard, industrial
Page 2-1
standard, vendor independent, and text-like. The format should be adapted to the type of data. Appendix 7
describes the way in which these files should be constructed.
The list of agreed to formats will be updated as technology evolves and new requirements arise. XML will
be the preferred format for all types of data.
Common Formats
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.
Regional Use of Other Formats

Regulatory authorities and applicants could agree to use other formats regionally (i.e., non-common
formats or uses of the common formats in a different way from above). The use of other formats is
discouraged and the intention is to use as much as possible the common formats. The intention of the use of
other formats is for transition.
There are two classes of transitions:

• Legacy Transition: from the past to the present (i.e., old formats to present formats.)
• Future Transition: from the present to the future (i.e., from present formats to new formats.) The new
formats would normally be candidates for common formats.
Links
CTD cross-references can be supported in the eCTD through the use of hyperlinks. Links among objects in
the eCTD submission should be relative. The intention is to make the eCTD submission self-contained. All
literature references introduced by the applicant should be included in the submission.
One can always point to a file. The capacity to point to a specific location within a file depends on the
linking technology. Different formats allow for the use of different linking technology. See Appendix 7.
Presentation
Presentation is closely associated with formats. To associate a Stylesheet with a file usually one has to use a
linking technology. The linking between Stylesheet (which could be in a separate file) and a data file
should be relative. In addition, there is the dimension of media. One file could have several Stylesheets; the
one used depends on the media. For example, there could be one presentation for the screen and another for
paper.
Checksums
The eCTD submission should contain checksums for each individual file including a checksum file for the
eCTD XML instance. Initially, the MD5 Message-Digest Algorithm (MD5) should be used for this
purpose. Including a checksum for each individual file provides a number of benefits including:
• The integrity of each file can be verified by comparing the checksum submitted with the file and
the computed checksum.
• The checksum can be used to verify that the file has not been altered in the historical archive of
the regulatory authority. This is especially useful as the files are migrated from one storage
medium to another, as in the case of backup to magnetic tape storage.
Element to File Directory Mapping

The following rules are recommended:
Page 2-2
• The rules below for the file and directories take precedence.
• Add the corresponding extension to the file.
• If appropriate, use a reasonable abbreviation.
File Extension
All files should have one and only one file extension. The file extension should be used to indicate the
format of the file. For example:
hello.pdf PDF
hello.rtf RTF
The mapping between formats and extensions are:
IANA nomenclature
text/css css
text/html html or htm
text/xml xml
application/pdf pdf
application/rtf rtf
application/vnd.ms-excel xls
image/jpeg jpg
image/png png
image/gif gif
Non IANA nomenclature

DTD dtd
XPT (SAS) xpt
XSL xsl
The eCTD submission could use formats not registered with the Internet Assigned Numbers Authority
(IANA).
The presence of a format in this list does not imply that it would be considered an acceptable format. For
formats absent from this list, widely used mapping between the formats and the extensions should be used.
Future direction: if a mechanism (e.g., standard) becomes available that associates the formats with file
extension, it should be considered for this specification.
Name
Name is a token composed of the following characters:
• Letters "a" to "z" [U+0061 to U+007A].
• Digits "0" to "9" [U+0030 to U+0039].
• "-" [HYPHEN-MINUS, U+002D].
The notation "U+" refers to the Unicode [UNICODE] notation.
This Specification does not provide for Japanese characters in file and folder names.
Examples of correct names (only the name without the extension):

part-b
myfile
hello
Examples of incorrect names (only the name without the extension):

part a (' ' ; SPACE is not allowed)
Page 2-3
myfile.xml ('.' ; FULL STOP is not allowed)
hello:pdf (':' ; COLON is not allowed)
part_a (‘_’, LOW LINE is not allowed)
Parta (UPPERCASE is not allowed)
Directory name is a name.
File name is one name followed by one name separated by a

'.' (FULL STOP, U+002E).
Correct file names (with the extension):
myfile.pdf
hello.cml
Incorrect file names (with the extension)::

a part.pdf (' '; SPACE is not allowed)
hello (missing extension)
hello:xml (':'; COLON is not allowed)
The maximum length of the name of a single folder or file is 64 characters including the extension. Only
lower case letters should be used in all file and directory names. The maximum length of a path is 230
characters, including file name, and extension. This allows regulators 26 characters to add to the path in
their review environments. Consult regional guidance for further restrictions on the maximum path length.
If the path exceeds the 230 character limit or the regionally-defined limit, then folder and file names
created by the applicant should be abbreviated. If further reduction is still called for, the file and folder
names recommended in Appendix 4 should be abbreviated. Applicants should also consult regional media
formats and M2 EWG recommendations for possible folder limits imposed by the media.
Document name is the first name in the file name. For example, “docname” in the file name
“docname.ext”.
Character encoding
The character encoding (charset) in order of preference is:
• Unicode UTF-8, Unicode 16 bits [ISO-10646].
• ISO-8859-1 (Latin-1) or appropriate ISO-8859-x; e.g., ISO-8859-7 for Greek.
• The appropriate SHIFT_JIS.
• Other character encoding agreed upon regionally by the regulatory authority and applicant.
References
[CML] Chemical Markup Language
http://cml.sourceforge.net
[CSS2] Cascading Style Sheets, level 2

http://www.w3.org/TR/REC-CSS2
[ECMAScript] ECMAScript Language Specification, 3rd edition. ECMA- 262

http://www.ecma-international.org/publications/standards/Ecma-262.htm
[EXCEL] Microsoft Excel

http://www.microsoft.com/office/excel/default.htm
[GIF] Graphics Interchange Format

http://tronche.com/computer-graphics/gif/gif89a.html
Page 2-4
[HTML] HTML 4.01 Specification
http://www.w3.org/TR/html4
[IANA] Internet Assigned Numbers Authority

http://www.iana.org
[IMT] Internet Media Types

http://www.iana.org/assignments/media-types/
[ISO-10646] Information Technology -- Universal Multiple-Octet Coded

Character Set (UCS) -- Part 1: Architecture and Basic Multilingual
Plane, ISO/IEC 10646-1:1993
[ISO-639] Codes for the representation of names of languages

ISO 639:1988.
http://www.oasis-open.org/cover/iso639a.html
[JPEG] Joint Photographic Experts Group

http://www.jpeg.org/public/wg1n1807.txt
[MD5] The MD5 Message-Digest Algorithm

http://ietf.org/rfc/rfc1321.txt
[PDF] Portable Document Format

http://www.adobe.com/devnet/pdf/pdf_reference.html
[PNG] PNG (Portable Network Graphics) Specification Version 1.0

http://www.w3.org/TR/REC-png.html
[RTF] Rich Text Format (RTF) Specification, version 1.6

http://msdn.microsoft.com/library/specs/rtfspec.htm
[SVG] Scalable Vector Graphics (SVG) 1.0 Specification (work in progress)

http://www.w3.org/TR/1999/WD-SVG-19991203
[UNICODE] Unicode Consortium

http://www.unicode.org
[XHTML] XHTML 1.0: The Extensible HyperText Markup Language

http://www.w3.org/TR/WD-html-in-xml
[XML] Extensible Markup Language (XML) 1.0 (Second Edition)

http://www.w3.org/TR/REC-xml.html
[XSL] Extensible Stylesheet Language (XSL)

Version 1.0 W3C Recommendation 15 October 2001
http://www.w3.org/TR/WD-xsl
[XSLT] XSL Transformations

http://www.w3.org/TR/xslt.html
Page 2-5
Appendix 3: General Considerations for the CTD Modules
Introduction
Documents that are provided in the different modules should be formatted as defined by the ICH Common
Technical Document. There should also be consistency in the way navigational aids are provided. Within
each document, bookmarks and hypertext links from the table of contents should be provided to all tables,
figures, publications, and appendices.
Hypertext links should be provided throughout the body of these documents to aid efficient navigation to
annotations, related sections, publications, appendices, tables, and figures that are not located on the same
page. CTD cross-references can be supported in the eCTD through the use of hyperlinks. If a list of
references is included at the end of a document, there should be hypertext links to the appropriate
publication.
Documents should be generated from electronic source documents and not from scanned material, except
where access to the source electronic file is unavailable or where a signature is called for.
Folder and File Naming Conventions

Recommended, but optional, folder and file names are presented in this specification. These could be used
in most cases, however applicants can modify this specification where appropriate. 1 For example, it is
generally acceptable to include an additional folder for information where an appropriate folder name is
unavailable in the eCTD specification or to provide for additional file organization where the recommended
foldering is inadequate. It is recommended that applicants maintain folder names listed in this specification.
This should not be interpreted to mean that the actual eCTD XML DTD should be changed or altered in
any way.
The maximum length of the name of a single folder or file is 64 characters including the extension. Folder
or file names should be written in lower case only. All files should have one and only one file extension.
The file extension should be used to indicate the format of the file. More details on the naming conventions
are given in Appendix 2, and examples in Appendix 4.
Filenames provided in the eCTD are optional. To assist the reviewer when several similar files are open at
the same time, it can be appropriate to consider alternative naming conventions that could provide unique,
understandable filenames. The general provisions for naming of files are in Appendix 2 of the
Specification.
Typically, the file name would be the applicant’s internal numbering or naming convention for the studies.
The following table gives an example of how files could be named.
1
Regulatory authorities should be notified of additions and changes to the folder structure according to
regional guidance.
Page 3-1
Table 3-1
Description File Name
Study Report 1 study-report-1.pdf
Study Report 2 study-report-2.pdf
… …
Study Report n study-report-n.pdf
Screenshots and Folder Hierarchy

Screenshots are provided in the following chapters for all modules down to the level of hierarchy as
described in this appendix. The representation in module 3 is in alphabetical order due to the nature of the
computer operating system and is therefore not entirely consistent with the sequence of the CTD. In a Web
browser the content will appear in the order of the CTD table of contents.
Detailed options on the folders and files are provided in Appendix 4 in case the applicant chooses to submit
more granular documents. It is not mandatory to use the full folder hierarchy. Empty directories can be
omitted; however, when the content is expected, justification should be provided as to why it is missing in
accordance with regional guidance.
Module 1 Administrative Information and Prescribing Information

The name of the folder for module 1 should be m1.
This module contains administrative information that is unique for each region. Regional guidance will
provide the specific instructions on how to provide the administrative forms and detailed prescribing
information. Please refer to Appendix 5 when preparing module 1.
Module 2 Summaries
The files in this module should be provided as PDF text with the exception of a few embedded images,
when needed. The name of the folder for module 2 should be m2. The folders in module 2 should be named
as follows but can be further reduced or omitted to minimize path length issues.
Table 3-2
Section in Description Folder Name
CTD
2.2 Introduction 22-intro
2.3 Quality overall summary 23-qos
2.4 Nonclinical Overview 24-nonclin-over
2.5 Clinical Overview 25-clin-over
2.6 Nonclinical Written and Tabulated 26-nonclin-sum

Summaries
2.7 Clinical summary 27-clin-sum
A representative folder hierarchy for module 2 is presented in the screenshot in figure 3-1.
Page 3-2
Figure 3-1 Screenshot representation of the folder structure of module 2
Page 3-3
Module 3 Quality
The name of the folder for module 3 should be m3. The folders in module 3 should be named as follows but
can be further reduced or omitted to minimize path length issues.
Table 3-3
CTD
3.2 Body of Data 32-body-data
3.2.S Drug Substance 32s-drug-sub
3.2.S Drug Substance [Drug Substance Name] substance-1-manufacturer-1

[Manufacturer] 2
3.2.S.1 General Information (name, manufacturer) 32s1-gen-info
3.2.S.2 Manufacture (name, manufacturer) 32s2-manuf
3.2.S.3 Characterisation (name, manufacturer) 32s3-charac
3.2.S.4 Control of Drug Substance (name, 32s4-contr-drug-sub

manufacturer)
3.2.S.4.1 Specification (name, manufacturer) 32s41-spec
3.2.S.4.2 Analytical Procedures (name, manufacturer) 32s42- analyt-proc
3.2.S.4.3 Validation of Analytical Procedures (name, 32s43-val-analyt-proc

manufacturer)
3.2.S.4.4 Batch Analyses (name, manufacturer) 32s44-batch-analys
3.2.S.4.5 Justification of Specification (name, 32s45-justif-spec

manufacturer)
3.2.S.5 Reference Standards or Materials (name, 32s5-ref-stand
manufacturer)
3.2.S.6 Container Closure System (name, 32s6-cont-closure-sys
manufacturer)
3.2.S.7 Stability (name, manufacturer) 32s7-stab
3.2.P Drug Product (name, dosage form) 3 32p-drug-prod
3.2.P Drug Product (name, dosage form) - Name product-1
3.2.P.1 Description and Composition of the Drug 32p1-desc-comp

Product (name, dosage form)
3.2.P.2 Pharmaceutical Development (name, dosage 32p2-pharm-dev
form)
2
Each drug substance-manufacturer should be placed in a separate subordinate folder. Folders and files
should be created for each drug substance-manufacturer section included in the submission in accordance
with the hierarchy identified in the following chapters.
3
Each drug product should be placed in a separate subordinate folder. Folders and files should be created
for each drug product section included in the submission in accordance with the hierarchy identified in the
following chapters. Reference should be made to regional guidance to determine whether the inclusion of
multiple products within a single application is considered appropriate.
Page 3-4
CTD
3.2.P.3 Manufacture (name, dosage form) 32p3-manuf
3.2.P.4 Control of Excipients (name, dosage form) 32p4-contr-excip
3.2.P.4 Control of Excipients (name, dosage form) - excipient-1

Excipient 1
3.2.P.5 Control of Drug Product (name, dosage form) 32p5-contr-drug-prod
3.2.P.5.1 Specification(s) (name, dosage form) 32p51-spec
3.2.P.5.2 Analytical Procedures (name, dosage form) 32p52-analyt-proc
3.2.P.5.3 Validation of Analytical Procedures (name, 32p53-val-analyt-proc

dosage form)
3.2.P.5.4 Batch Analyses (name, dosage form) 32p54-batch-analys
3.2.P.5.5 Characterisation of Impurities (name, dosage 32p55-charac-imp

form)
3.2.P.5.6 Justification of Specifications (name, dosage 32p56-justif-spec
form)
3.2.P.6 Reference Standards or Materials (name, dosage 32p6-ref-stand
form)
3.2.P.7 Container Closure System (name, dosage form) 32p7-cont-closure-sys
3.2.P.8 Stability (name, dosage form) 32p8-stab
3.2.A Appendices 32a-app
3.2.A.1 Facilities and Equipment (name, manufacturer) 32a1-fac-equip
3.2.A.2 Adventitious Agents Safety Evaluation (name, 32a2-advent-agent

dosage form, manufacturer)
3.2.A.3 Excipients- Name 4 32a3-excip-name-1
3.2.R Regional Information 5 32r-reg-info
3.3 Literature References 33-lit-ref
4
The folder name should include the name of the excipient, abbreviated as necessary to remain within the
64 character limit.
5
This folder should be included where regional information is appropriate. Reference should be made to
regional guidance for the types of information to be included in this section.
Page 3-5
Page 3-6
Module 4 Nonclinical Study Reports
Table 3-4
Section in
Description Folder Name
CTD
4.2 Study Reports 42-stud-rep
4.2.1 Pharmacology 421-pharmacol
4.2.1.1 Primary Pharmacodynamics 4211-prim-pd
4.2.1.2 Secondary Pharmacodynamics 4212-sec-pd
4.2.1.3 Safety Pharmacology 4213-safety-pharmacol
4.2.1.4 Pharmacodynamic Drug Interactions 4214-pd-drug-interact
4.2.2 Pharmacokinetics 422-pk

Analytical Methods and Validation Reports (if
4.2.2.1 4221-analyt-met-val
separate reports are available)
4.2.2.2 Absorption 4222-absorp
4.2.2.3 Distribution 4223-distrib
4.2.2.4 Metabolism 4224-metab
4.2.2.5 Excretion 4225-excr
4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical) 4226-pk-drug-interact
4.2.2.7 Other Pharmacokinetic Studies 4227-other-pk-stud
4.2.3 Toxicology 423-tox

Single-Dose Toxicity (in order by species, by
4.2.3.1 4231-single-dose-tox
route)
Repeat-Dose Toxicity (in order by species, by
4.2.3.2 route, by duration, including supportive 4232-repeat-dose-tox
toxicokinetics evaluations)
4.2.3.3 Genotoxicity 4233-genotox
4.2.3.3.1 In vitro 42331-in-vitro

In vivo (including supportive toxicokinetics
4.2.3.3.2 42332-in-vivo
evaluations)
Carcinogenicity (including supportive
4.2.3.4 4234-carcigen
Long-term studies (in order by species,
including range-finding studies that cannot be
4.2.3.4.1 42341-lt-stud
appropriately included under repeat-dose
toxicity or pharmacokinetics)
Page 3-7
Section in
CTD
Short-or medium-term studies (including range-
finding studies that cannot be appropriately
4.2.3.4.2 42342-smt-stud
included under repeat-dose toxicity or
pharmacokinetics)
4.2.3.4.3 Other studies 42343-other-stud
Reproductive and Developmental Toxicity
4.2.3.5 (including range-finding studies and supportive 4235-repro-dev-tox
4.2.3.5.1 Fertility and early embryonic development 42351-fert-embryo-dev
4.2.3.5.2 Embryo-fetal development 42352-embryo-fetal-dev

Prenatal and postnatal development, including
4.2.3.5.3 42353-pre-postnatal-dev
maternal function
Studies in which the offspring (juvenile
4.2.3.5.4 42354-juv
animals) are dosed and/or further evaluated
4.2.3.6 Local Tolerance 4236-loc-tol
4.2.3.7 Other Toxicity Studies (if available) 4237-other-tox-stud
4.2.3.7.1 Antigenicity 42371-antigen
4.2.3.7.2 Immunotoxicity 42372-immunotox
4.2.3.7.3 Mechanistic studies (if not included elsewhere) 42373-mechan-stud
4.2.3.7.4 Dependence 42374-dep
4.2.3.7.5 Metabolites 42375-metab
4.2.3.7.6 Impurities 42376-imp
4.2.3.7.7 Other 42377-other
Page 3-8
Page 3-9
Module 5 Clinical Study Reports
Table 3-5
Section in
CTD
5.2 Tabular Listing of all Clinical Studies 52-tab-list
5.3 Clinical Study Reports 53-clin-stud-rep
5.3.1 Reports of Biopharmaceutic Studies 531-rep-biopharm-stud
5.3.1.1 Bioavailability (BA) Study Reports 5311-ba-stud-rep
"Study Report 1" study-report-1

Comparative BA and Bioequivalence (BE)
5.3.1.2 5312-compar-ba-be-stud-rep
Study Reports
5.3.1.3 In vitro – In vivo Correlation Study Reports 5313-in-vitro-in-vivo-corr-stud-rep

Reports of Bioanalytical and Analytical
5.3.1.4 5314-bioanalyt-analyt-met
Methods for Human Studies

Reports of Studies Pertinent to
5.3.2 532-rep-stud-pk-human-biomat
Pharmacokinetics using Human Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports 5321-plasma-prot-bind-stud-rep
Page 3-10
Section in
CTD
Reports of Hepatic Metabolism and Drug
5.3.2.2 5322-rep-hep-metab-interact-stud
Interaction Studies

Reports of Studies Using Other Human
5.3.2.3 5323-stud-other-human-biomat
Biomaterials

Reports of Human Pharmacokinetic (PK)
5.3.3 533-rep-human-pk-stud
Studies
Healthy Subject PK and Initial Tolerability
5.3.3.1 5331-healthy-subj-pk-init-tol-stud-rep
Study Reports

Patient PK and Initial Tolerability Study
5.3.3.2 5332-patient-pk-init-tol-stud-rep
Reports
5.3.3.3 Intrinsic Factor PK Study Reports 5333-intrin-factor-pk-stud-rep
5.3.3.4 Extrinsic Factor PK Study Reports 5334-extrin-factor-pk-stud-rep
5.3.3.5 Population PK Study Reports 5335-popul-pk-stud-rep
Page 3-11
Section in
CTD

Reports of Human Pharmacodynamic (PD)
5.3.4 534-rep-human-pd-stud
Studies
5.3.4.1 Healthy Subject PD and PK/PD Study Reports 5341-healthy-subj-pd-stud-rep
5.3.4.2 Patient PD and PK/PD Study Reports 5342-patient-pd-stud-rep

535-rep-effic-safety-stud
5.3.5 Reports of Efficacy and Safety Studies
Reports of Efficacy and Safety Studies –
5.3.5 indication-1
Indication Name
Study Reports of Controlled Clinical Studies
5.3.5.1 5351-stud-rep-contr
Pertinent to the Claimed Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies 5352-stud-rep-uncontr

Reports of Analyses of Data from More than
5.3.5.3 5353-rep-analys-data-more-one-stud
One Study
5.3.5.4 Other Study Reports 5354-other-stud-rep
Page 3-12
Section in
CTD
5.3.6 Reports of Postmarketing Experience 536-postmark-exp

Case Report Forms and Individual Patient
5.3.7 537-crf-ipl
Listings 6
“Study Report 1” study-report-1
The CTD organization provides locations for case report forms and individual patient data listings in
Module 5.3.7 and for literature references in Module 5.4.
In the eCTD, files for publications and literature references should be located in the folder for Module 5.4.
However, in the index.xml file the leaf elements for these publications and literature references should be
included under the same heading as the other study report files with additional information included
through use of the study tagging file, if applicable in that region. In addition, a repeat of the leaf element
should be placed under the heading for 5.4 Literature References.
Case report forms, data sets and individual patient data listings should be organized according to regional
guidance.
6
The content of this folder should follow regional guidance.
Page 3-13
Page 3-14
Figure 3-4 Screenshot representation of the folder structure of module 5 (cont)
Page 3-15
Figure 3-4 Screenshot representation of the folder structure of module 5 (cont)
Page 3-16
Appendix 4: File Organization for the eCTD
Each item in the file organization table that is listed in this appendix includes the information outlined below:
Sequential Each item in the table has a unique sequentially assigned reference number. These reference numbers can
number change with each version of this appendix.
Number CTD section number
Title CTD title
Element Element name in the Backbone
File/Directory Relative path of the File/Directory. The file extension corresponds to the file type; i.e., the “pdf” extension is
only illustrative. Refer to Table 6.1, Appendix 6, for details for the head of the path name
Comment Comments
The file organization table covers files that constitute the backbone itself plus any additional files to make the submission complete, readable and processable. The file and
folder names shown within modules 2-5 are not mandatory, but recommended, and can be further reduced or omitted to avoid path length issues. Refer to the M4
Organisation Document: Granularity Annex in the ICH guidance on 'Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human
Use' for information on where multiple documents/files are appropriate in each section or subsection of the eCTD. This describes what is considered to be the appropriate
granularity for each section of the CTD and hence the eCTD. Where there is no definition provided in the organisation document, applicants are free to construct the dossier
as they see fit with respect to document granularity.
Where file and folder names are presented in italics applicants would substitute these with appropriate file names in accordance with their own naming conventions.
Page 4-1
Table 4-1
Number
Title
1 Element
File index.xml
Comment This is the Backbone
Number
Title
2 Element
File index-md5.txt
Comment The MD5 of the Backbone
Page 4-2
Number 1
Title Administrative Information and Prescribing Information
3 Element m1-administrative-information-and-prescribing-information
Directory m1
Comment Only one of the regional directories is needed
Number
Title
Element
4
Directory m1/eu
EU directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to regional
Comment
guidance for details
Number
Title
Element
5
Directory m1/jp
Japan directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to
Comment
regional guidance for details
Number
Title
Element
6
Directory m1/us
US directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to regional
Comment
guidance for details
Number
Title
Element
7
Directory m1/xx
xx directory; where xx is a two character country code from ISO-3166-1. In addition to the appropriate regional documents, the regional
Comment
xml instance should be located in this folder. Refer to regional guidance for details
Page 4-3
Number 2
Title Common Technical Document Summaries
8 Element m2-common-technical-document-summaries
Directory m2
Comment
Number 2.2
Title Introduction
9 Element m2-2-introduction
Directory m2/22-intro
Comment
Number 2.2
Title Introduction
File m2/22-intro/introduction.pdf
Comment
Number 2.3
Title Quality Overall Summary
Element m2-3-quality-overall-summary
11
Directory
m2/23-qos
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Comment
Overall Summary
Number 2.3
Title Introduction
File m2/23-qos/introduction.pdf
Comment
13 Number 2.3.S
Title Drug Substance - Name - Manufacturer
Element m2-3-s-drug-substance
File m2/23-qos/drug-substance.pdf
Page 4-4
Comment Overall Summary
Where there are more than one drug substance and/or manufacturer, separate files can be provided for each.
Number 2.3.P
Title Drug Product -Name
Element m2-3-p-drug-product
File m2/23-qos/drug-product-name.pdf
14
Overall Summary
Comment
Refer to regional guidance for definition of what constitutes a drug product and the acceptability of more than one drug product in an
application. Where more than one drug product is acceptable in an application, a separate file can be provided for each drug product.
Number 2.3.A
Title Appendices
Element m2-3-a-appendices
15
File m2/23-qos/appendices.pdf
Comment
Overall Summary
Number 2.3.R
Title Regional Information
Element m2-3-r-regional-information
16
File m2/23-qos/regional-information.pdf
Comment
Overall Summary
Number 2.4
Title Nonclinical Overview
17 Element m2-4-nonclinical-overview
Directory m2/24-nonclin-over
Comment
Number 2.4
Title Nonclinical Overview
Element m2-4-nonclinical-overview
18
File m2/24-nonclin-over/nonclinical-overview.pdf
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
Comment
the document to these sub-headings.
Page 4-5
Number 2.5
Title Clinical Overview
19 Element m2-5-clinical-overview
Directory m2/25-clin-over
Comment
Number 2.5
Title Clinical Overview
Element m2-5-clinical-overview
20
File m2/25-clin-over/clinical-overview.pdf
Comment
Number 2.6
Title Nonclinical Written and Tabulated Summaries
21 Element m2-6-nonclinical-written-and-tabulated-summaries
Directory m2/26-nonclin-sum
Comment
Number 2.6.1
Title Introduction
22 Element m2-6-1-introduction
File m2/26-nonclin-sum/introduction.pdf
Comment
Number 2.6.2
Title Pharmacology Written Summary
Element m2-6-2-pharmacology-written-summary
23
File m2/26-nonclin-sum/pharmacol-written-summary.pdf
Comment
Number 2.6.3
Title Pharmacology Tabulated Summary
24 Element m2-6-3-pharmacology-tabulated-summary
File m2/26-nonclin-sum/pharmacol-tabulated-summary.pdf
Comment Should have further navigation via bookmarks
25 Number 2.6.4
Page 4-6
Title Pharmacokinetics Written Summary
Element m2-6-4-pharmacokinetics-written-summary
File m2/26-nonclin-sum/pharmkin-written-summary.pdf
Comment
Number 2.6.5
Title Pharmacokinetics Tabulated Summary
26 Element m2-6-5-pharmacokinetics-tabulated-summary
File m2/26-nonclin-sum/pharmkin-tabulated-summary.pdf
Number 2.6.6
Title Toxicology Written Summary
Element m2-6-6-toxicology-written-summary
27
File m2/26-nonclin-sum/toxicology-written-summary.pdf
Comment
Number 2.6.7
Title Toxicology Tabulated Summary
28 Element m2-6-7-toxicology-tabulated-summary
File m2/26-nonclin-sum/toxicology-tabulated-summary.pdf
Number 2.7
Title Clinical Summary
29 Element m2-7-clinical-summary
Directory m2/27-clin-sum
Comment
Number 2.7.1
Title Summary of Biopharmaceutic Studies and Associated Analytical Methods
Element m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analytical-methods
30
File m2/27-clin-sum/summary-biopharm.pdf
Comment
31 Number 2.7.2
Title Summary of Clinical Pharmacology Studies
Page 4-7
Elementm2-7-2-summary-of-clinical-pharmacology-studies
File m2/27-clin-sum/summary-clin-pharm.pdf
Comment
Number 2.7.3
Title Summary of Clinical Efficacy – Indication
Element m2-7-3-summary-of-clinical-efficacy
File m2/27-clin-sum/summary-clin-efficacy-indication.pdf
The file name should always include the indication being claimed (abbreviated if appropriate) e.g., 'summary-clin-efficacy-asthma.pdf'.
Where there is more than one indication (e.g., asthma & migraine) then the first indication has a file name 'summary-clin-efficacy-
asthma.pdf' and the second 'summary-clin-efficacy-migraine.pdf'. Typically, this document should consist of a single file. The CTD defines
32 further heading levels and navigation should be provided within the document to these sub-headings.
The ‘indication’ attribute in the backbone should be consistent with that used in the filename but can be different. For example, an
Comment
‘indication’ attribute value of ‘Non-Small Cell Lung Cancer’ could be expressed as ‘NSCLC’ in the filename for that document (i.e.,
summclineff-nsclc.pdf). There is currently no standard terminology list for ‘indication’ and applicants should choose these attributes
carefully as they can not be easily changed during the life cycle of the application. The only way this can be accomplished currently is to
delete all the leaf elements with the incorrect attribute value and provide new leaf elements for those files with the modified attribute value.
Applicants should consult with the regional authority before attempting to modify these attributes to discuss the appropriateness of, and
approach to be taken for, this type of change.
Number 2.7.4
Title Summary of Clinical Safety
Element m2-7-4-summary-of-clinical-safety
33
File m2/27-clin-sum/summary-clin-safety.pdf
Comment
Number 2.7.5
Title Literature References
34 Element m2-7-5-literature-references
File m2/27-clin-sum/literature-references.pdf
Comment
35 Number 2.7.6
Title Synopses of Individual Studies
Element m2-7-6-synopses-of-individual-studies
Page 4-8
File m2/27-clin-sum/synopses-indiv-studies.pdf
These synopses should already be located in the Clinical Study Reports in Module 5 and should not, therefore, be repeated in Module 2. It is
Comment
considered sufficient to provide hyperlinks from the listing of the studies, located here, to the locations of the synopses in Module 5.
Page 4-9
Number 3
Title Quality
36 Element m3-quality
Directory m3
Comment Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for Module 3
Number 3.2
Title Body of Data
37 Element m3-2-body-of-data
Directory m3/32-body-data
Comment
Number 3.2.S
Title Drug Substance
38 Element m3-2-s-drug-substance
Directory m3/32-body-data/32s-drug-sub
Comment
Number 3.2.S
Title Drug Substance - Drug Substance Name - Manufacturer
Element m3-2-s-drug-substance
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1
In this section, it can be helpful if the folder name includes the name of the drug substance and manufacturer. This applies particularly when
there are multiple drug substances and/or manufacturers. When naming folders, attention should be paid to the length of the name of the
folder on the overall length of the full path. Abbreviations can help control the length of the path.
39
The ‘substance’ and ‘manufacturer’ attribute values in the backbone should be consistent with that used in the folder name but can be
Comment different. For example, a ‘manufacturer’ attribute value of ‘Company XXX, City Name, Country Name’ could be expressed as ‘xxx’ in the
folder name. There is currently no standard terminology list for these attributes and applicants should choose these attributes carefully as
they can not be easily changed during the life cycle of the application. The only way this can be accomplished currently is to delete all the
leaf elements with the incorrect attribute value and provide new leaf elements for those files with the modified attribute value. Applicants
should consult with the regional authority before attempting to modify these attributes to discuss the appropriateness of, and approach to be
taken for, this type of change.
40 Number 3.2.S.1
Title General Information (name, manufacturer)
Page 4-10
Element m3-2-s-1-general-information
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info
Comment
Number 3.2.S.1.1
Title Nomenclature (name, manufacturer)
41 Element m3-2-s-1-1-nomenclature
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/nomenclature.pdf
Comment
Number 3.2.S.1.2
Title Structure (name, manufacturer)
42 Element m3-2-s-1-2-structure
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/structure.pdf
Comment
Number 3.2.S.1.3
Title General Properties (name, manufacturer)
43 Element m3-2-s-1-3-general-properties
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/general-properties.pdf
Comment
Number 3.2.S.2
Title Manufacture (name, manufacturer)
44 Element m3-2-s-2-manufacture
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf
Comment
Number 3.2.S.2.1
Title Manufacturer(s) (name, manufacturer)
45 Element m3-2-s-2-1-manufacturer
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manufacturer.pdf
Comment For this document there should be only information regarding one manufacturer
Number 3.2.S.2.2
Title Description of Manufacturing Process and Process Controls (name, manufacturer)
46 Element m3-2-s-2-2-description-of-manufacturing-process-and-process-controls
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manuf-process-and-controls.pdf
Comment
Page 4-11
Number 3.2.S.2.3
Title Control of Materials (name, manufacturer)
47 Element m3-2-s-2-3-control-of-materials
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/control-of-materials.pdf
Comment
Number 3.2.S.2.4
Title Controls of Critical Steps and Intermediates (name, manufacturer)
48 Element m3-2-s-2-4-controls-of-critical-steps-and-intermediates
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/control-critical-steps.pdf
Comment
Number 3.2.S.2.5
Title Process Validation and/or Evaluation (name, manufacturer)
49 Element m3-2-s-2-5-process-validation-and-or-evaluation
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/process-validation.pdf
Comment
Number 3.2.S.2.6
Title Manufacturing Process Development (name, manufacturer)
50 Element m3-2-s-2-6-manufacturing-process-development
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manuf-process-development.pdf
Comment
Number 3.2.S.3
Title Characterisation (name, manufacturer)
51 Element m3-2-s-3-characterisation
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac
Comment
Number 3.2.S.3.1
Title Elucidation of Structure and Other Characteristics (name, manufacturer)
52 Element m3-2-s-3-1-elucidation-of-structure-and-other-characteristics
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac/elucidation-of-structure.pdf
Comment
53 Number 3.2.S.3.2
Title Impurities (name, manufacturer)
Element m3-2-s-3-2-impurities
Page 4-12
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac/impurities.pdf
Comment
Number 3.2.S.4
Title Control of Drug Substance (name, manufacturer)
54 Element m3-2-s-4-control-of-drug-substance
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub
Comment
Number 3.2.S.4.1
Title Specification (name, manufacturer)
55 Element m3-2-s-4-1-specification
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s41-spec
Comment
Number 3.2.S.4.1
Title Specification (name, manufacturer)
56 Element m3-2-s-4-1-specification
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s41-spec/specification.pdf
Comment
Number 3.2.S.4.2
Title Analytical Procedures (name, manufacturer)
Element m3-2-s-4-2-analytical-procedures
57
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, can be organized.
Comment
CTD numbering is not defined below this level (e.g., 3.2.S.4.2.1).
Number
Title Analytical Procedure-1
58 Element m3-2-s-4-2-analytical-procedures
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc/analytical-procedure-1.pdf
Comment
Number
Comment
Page 4-13
Number
Comment
Number 3.2.S.4.3
Title Validation of Analytical Procedures
Element m3-2-s-4-3-validation-of-analytical-procedures (name, manufacturer)
61
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, can be organized.
Comment
CTD numbering is not defined below this level (e.g., 3.2.S.4.3.1).
Number
Title Validation of Analytical Procedure-1
62 Element m3-2-s-4-3-validation-of-analytical-procedures
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc/validation-analyt-procedure-1.pdf
Comment
Number
Comment
Number
Comment
Number 3.2.S.4.4
Title Batch Analyses (name, manufacturer)
65 Element m3-2-s-4-4-batch-analyses
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s44-batch-analys
Comment
66 Number 3.2.S.4.4
Page 4-14
Title Batch Analyses (name, manufacturer)
Element m3-2-s-4-4-batch-analyses
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s44-batch-analys/batch-analyses.pdf
Comment
Number 3.2.S.4.5
Title Justification of Specification (name, manufacturer)
67 Element m3-2-s-4-5-justification-of-specification
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s45-justif-spec
Comment
Number 3.2.S.4.5
Title Justification of Specification (name, manufacturer)
68 Element m3-2-s-4-5-justification-of-specification
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s45-justif-spec/justification-of-specification.pdf
Comment
Number 3.2.S.5
Title Reference Standards or Materials (name, manufacturer)
69 Element m3-2-s-5-reference-standards-or-materials
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand
Comment
Number 3.2.S.5
Title Reference Standards or Materials (name, manufacturer)
70 Element m3-2-s-5-reference-standards-or-materials
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand/reference-standards.pdf
Comment Where a multiple file approach is taken for this section, the file names should indicate which reference standard is covered in the document.
Number 3.2.S.6
Title Container Closure System (name, manufacturer)
71 Element m3-2-s-6-container-closure-system
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys
Comment
72 Number 3.2.S.6
Title Container Closure System (name, manufacturer)
Element m3-2-s-6-container-closure-system
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys/container-closure-system.pdf
Page 4-15
Comment
Number 3.2.S.7
Title Stability (name, manufacturer)
73 Element m3-2-s-7-stability
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab
Comment
Number 3.2.S.7.1
Title Stability Summary and Conclusions (name, manufacturer)
74 Element m3-2-s-7-1-stability-summary-and-conclusions
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/stability-summary.pdf
Comment
Number 3.2.S.7.2
Title Post-approval Stability Protocol and Stability Commitment (name, manufacturer)
75 Element m3-2-s-7-2-post-approval-stability-protocol-and-stability-commitment
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/postapproval-stability.pdf
Comment
Number 3.2.S.7.3
Title Stability Data (name, manufacturer)
76 Element m3-2-s-7-3-stability-data
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/stability-data.pdf
Comment
Number 3.2.P
Title Drug Product (name, dosage form)
77 Element m3-2-p-drug-product
Directory m3/32-body-data/32p-drug-prod
Comment
78 Number 3.2.P
Title Drug Product (name, dosage form) – Name
Element m3-2-p-drug-product
Directory m3/32-body-data/32p-drug-prod/product-1
Page 4-16
In this section, it can be helpful if the folder name includes the name of the drug product. This applies particularly where there is more than
one drug product (e.g., powder for reconstitution and diluent); the first drug product would have a folder 'powder-for-reconstitution' and the
second, 'diluent'.
Refer to regional guidance for definition of what constitutes a drug product and the acceptability of more than one drug product in an
application.
Comment The ‘product-name’ attribute value in the backbone should be consistent with that used in the folder name but can be different. For
example, a ‘product-name’ attribute value of ‘Lyophilized Powder for Reconstitution’ could be expressed as ‘powder’ in the folder name.
There is currently no standard terminology list for these attributes and applicants should choose these attributes carefully as they can not be
easily changed during the life cycle of the application. The only way this can be accomplished currently is to delete all the leaf elements
with the incorrect attribute value and provide new leaf elements for those files with the modified attribute value. Applicants should consult
with the regional authority before attempting to modify these attributes to discuss the appropriateness of, and approach to be taken for, this
type of change.
Number 3.2.P.1
Title Description and Composition of the Drug Product (name, dosage form)
79 Element m3-2-p-1-description-and-composition-of-the-drug-product
Directory m3/32-body-data/32p-drug-prod/product-1/32p1-desc-comp
Comment
Number 3.2.P.1
Title Description and Composition of the Drug Product (name, dosage form)
80 Element m3-2-p-1-description-and-composition-of-the-drug-product
File m3/32-body-data/32p-drug-prod/product-1/32p1-desc-comp/description-and-composition.pdf
Comment
Number 3.2.P.2
Title Pharmaceutical Development (name, dosage form)
Element m3-2-p-2-pharmaceutical-development
81
Directory m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev
Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical
Comment
Development section.
82 Number 3.2.P.2
Title Pharmaceutical Development (name, dosage form)
Element m3-2-p-2-pharmaceutical-development
File m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev/pharmaceutical-development.pdf
Page 4-17
Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical
Comment
Development section.
Number 3.2.P.3
Title Manufacture (name, dosage form)
83 Element m3-2-p-3-manufacture
Directory m3/32-body-data/32p-drug-prod/product-1/32p3-manuf
Comment
Number 3.2.P.3.1
Title Manufacturer(s) (name, dosage form)
84 Element m3-2-p-3-1-manufacturers
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manufacturers.pdf
Comment
Number 3.2.P.3.2
Title Batch Formula (name, dosage form)
85 Element m3-2-p-3-2-batch-formula
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/batch-formula.pdf
Comment
Number 3.2.P.3.3
Title Description of Manufacturing Process and Process Controls (name, dosage form)
86 Element m3-2-p-3-3-description-of-manufacturing-process-and-process-controls
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manuf-process-and-controls.pdf
Comment
Number 3.2.P.3.4
Title Controls of Critical Steps and Intermediates (name, dosage form)
87 Element m3-2-p-3-4-controls-of-critical-steps-and-intermediates
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/control-critical-steps.pdf
Comment
Number 3.2.P.3.5
Title Process Validation and/or Evaluation (name, dosage form)
88 Element m3-2-p-3-5-process-validation-and-or-evaluation
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/process-validation.pdf
Comment The applicant has the option to submit one or multiple files, one for each validation or evaluation.
Page 4-18
Number 3.2.P.4
Title Control of Excipients (name, dosage form)
89 Element m3-2-p-4-control-of-excipients
Directory m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip
Comment
Number 3.2.P.4
Title Control of Excipients (name, dosage form) – Excipient
Element m3-2-p-4-control-of-excipients
Directory m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1
For a drug product containing more than one excipient, the information requested for sections 3.2.P.4.1 – 3.2.P.4.4 should be provided in its
entirety for each excipient. Refer to the ICH eCTD QA and Change Requests document, Q&A No.4 for additional suggestions on
structuring this section. For compendial excipient(s) without additional specification tests, it is appropriate to have all information in one
90 file, making sure to introduce a folder for each of new documents to avoid mixing files and folders at the same level. Non-compendial
excipients should follow the structure outlined below.
Comment
The ‘excipient’ attribute value in the backbone should be consistent with that used in the folder name but can be different. There is
currently no standard terminology list for these attributes and applicants should choose these attributes carefully as they can not be easily
changed during the life cycle of the application. The only way this can be accomplished currently is to delete all the leaf elements with the
incorrect attribute value and provide new leaf elements for those files with the modified attribute value. Applicants should consult with the
regional authority before attempting to modify these attributes to discuss the appropriateness of, and approach to be taken for, this type of
change.
Number 3.2.P.4.1
Title Specifications (name, dosage form)
91 Element m3-2-p-4-1-specifications
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/specifications.pdf
Comment See comment under 3.2.P.4.
Number 3.2.P.4.2
Title Analytical Procedures (name, dosage form)
92 Element m3-2-p-4-2-analytical-procedures
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/analytical-procedures.pdf
93 Number 3.2.P.4.3
Title Validation of Analytical Procedures (name, dosage form)
Element m3-2-p-4-3-validation-of-analytical-procedures
Page 4-19
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/validation-analyt-procedures.pdf
Number 3.2.P.4.4
Title Justification of Specifications (name, dosage form)
94 Element m3-2-p-4-4-justification-of-specifications
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/justification-of-specifications.pdf
Number 3.2.P.4.5
Title Excipients of Human or Animal Origin (name, dosage form)
95 Element m3-2-p-4-5-excipients-of-human-or-animal-origin
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipients-human-animal.pdf
Comment
Number 3.2.P.4.6
Title Novel Excipients (name, dosage form)
96 Element m3-2-p-4-6-novel-excipients
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/novel-excipients.pdf
Comment
Number 3.2.P.5
Title Control of Drug Product (name, dosage form)
97 Element m3-2-p-5-control-of-drug-product
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod
Comment
Number 3.2.P.5.1
Title Specification(s) (name, dosage form)
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec
Comment
Number 3.2.P.5.1
Title Specification(s) (name, dosage form)
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec/specifications.pdf
Comment
100 Number 3.2.P.5.2
Page 4-20
Title Analytical Procedures (name, dosage form)
Element m3-2-p-5-2-analytical-procedures
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
Comment
CTD numbering is not defined below this level (e.g., 3.2.P.5.2.1).
Number
Title Analytical Procedure – 1
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-1.pdf
Comment
Number
Comment
Number
Comment
Number 3.2.P.5.3
Title Validation of Analytical Procedures (name, dosage form)
104
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
Comment
CTD numbering is not defined below this level (e.g., 3.2.P.5.3.1).
Number
Title Validation of Analytical Procedures – 1
105 Element m3-2-p-5-3-validation-of-analytical-procedures
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc/validation-analytical-procedures-1.pdf
Comment
106 Number
Page 4-21
Comment
Number
107 Element m3-2-p-5-3-validation-of-analytical-procedures
Comment
Number 3.2.P.5.4
Title Batch Analyses (name, dosage form)
108 Element m3-2-p-5-4-batch-analyses
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p54-batch-analys
Comment
Number 3.2.P.5.4
Title Batch Analyses (name, dosage form)
109 Element m3-2-p-5-4-batch-analyses
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p54-batch-analys/batch-analyses.pdf
Comment
Number 3.2.P.5.5
Title Characterisation of Impurities (name, dosage form)
110 Element m3-2-p-5-5-characterisation-of-impurities
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p55-charac-imp
Comment
Number 3.2.P.5.5
Title Characterisation of Impurities (name, dosage form)
111 Element m3-2-p-5-5-characterisation-of-impurities
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p55-charac-imp/characterisation-impurities.pdf
Comment
Number 3.2.P.5.6
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec
Comment
Page 4-22
Number 3.2.P.5.6
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec/justification-of-specifications.pdf
Comment
Number 3.2.P.6
Title Reference Standards or Materials (name, dosage form)
114 Element m3-2-p-6-reference-standards-or-materials
Directory m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand
Comment
Number 3.2.P.6
Title Reference Standards or Materials (name, dosage form)
115 Element m3-2-p-6-reference-standards-or-materials
File m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand/reference-standards.pdf
Comment When a multiple file approach is taken for this section, the file names should indicate which reference standard is covered in the document.
Number 3.2.P.7
Title Container Closure System (name, dosage form)
116 Element m3-2-p-7-container-closure-system
Directory m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys
Comment
Number 3.2.P.7
Title Container Closure System (name, dosage form)
117 Element m3-2-p-7-container-closure-system
File m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys/container-closure-system.pdf
Comment
Number 3.2.P.8
Title Stability (name, dosage form)
118 Element m3-2-p-8-stability
Directory m3/32-body-data/32p-drug-prod/product-1/32p8-stab
Comment
119 Number 3.2.P.8.1
Title Stability Summary and Conclusion (name, dosage form)
Element m3-2-p-8-1-stability-summary-and-conclusion
Page 4-23
File m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-summary.pdf
Comment
Number 3.2.P.8.2
Title Post-approval Stability Protocol and Stability Commitment (name, dosage form)
120 Element m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment
File m3/32-body-data/32p-drug-prod/product-1/32p8-stab/postapproval-stability.pdf
Comment
Number 3.2.P.8.3
Title Stability Data (name, dosage form)
121 Element m3-2-p-8-3-stability-data
File m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-data.pdf
Comment
Number 3.2.A
Title Appendices
122 Element m3-2-a-appendices
Directory m3/32-body-data/32a-app
Comment
Number 3.2.A.1
Title Facilities and Equipment (name, manufacturer)
Element m3-2-a-1-facilities-and-equipment
123 Directory m3/32-body-data/32a-app/32a1-fac-equip
Several reports are likely to be included in this appendix. The organisation is left to the applicant to define. However, where there is more
Comment than one manufacturer a folder should be created for each manufacturer and the identity of the manufacturer included in the directory name.
CTD numbering is not defined below this level (e.g., 3.2.A.1.1).
Number
Title Facilities and Equipment Report 1
124 Element m3-2-a-1-facilities-and-equipment
File m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-1.pdf
Comment
125 Number
Element m3-2-a-1-facilities-and-equipment
Page 4-24
Comment
Number
126 Element m3-2-a-1-facilities-and-equipment
Comment
Number 3.2.A.2
Title Adventitious Agents Safety Evaluation (name, dosage form, manufacturer)
Element m3-2-a-2-adventitious-agents-safety-evaluation
127 Directory m3/32-body-data/32a-app/32a2-advent-agent
Nonviral adventitious agents reports should be placed in this folder. For viral adventitious agents the following sub-folder structure should
Comment be used. However, where there is more than one drug substance, drug product, manufacturer etc., a directory should be created for each
option and its identity included in the directory name. CTD numbering is not defined below this level (e.g., 3.2.A.2.1).
Number
Title Adventitious Agents Safety Evaluation Report 1
128 Element m3-2-a-2-adventitious-agents-safety-evaluation
File m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-1.pdf
Comment
Number
Comment
Number
Comment
131 Number 3.2.A.3
Title Excipients – Name
Element m3-2-a-3-excipients
Directory m3/32-body-data/32a-app/32a3-excip-name-1
Page 4-25
The name of any novel excipient should be included in the folder name. If there is more than one novel excipient then each folder should
have unique identification through the use of different names e.g., '32a3-excip-name-1' and '32a3-excip-name-2'.
Comment
The directory/file structure would typically follow that of the drug substance section in Module 3.2.S. Refer to regional guidances for the
need for such information to be included in the submission directly as opposed to its inclusion in a Drug Master File.
Number 3.2.R
Title Regional Information
132 Element m3-2-r-regional-information
Directory m3/32-body-data/32r-reg-info
Comment Refer to the M4 Organisation Document: Granularity Annex for the approach to take with this section.
Number 3.3
Element m3-3-literature-references
133
Directory m3/33-lit-ref
Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference). CTD numbering is not defined
Comment
below this level (e.g., 3.3.1).
Number
Title Reference 1
134 Element m3-3-literature-references
File m3/33-lit-ref/reference-1.pdf
Comment
Number
Title Reference 2
Comment
Number
Title Reference 3
Comment
Page 4-26
Number 4
Title Nonclinical Study Reports
137 Element m4-nonclinical-study-reports
Directory m4
Comment
Number 4.2
Title Study Reports
138 Element m4-2-study-reports
Directory m4/42-stud-rep
Comment
Number 4.2.1
Title Pharmacology
139 Element m4-2-1-pharmacology
Directory m4/42-stud-rep/421-pharmacol
Comment
Number 4.2.1.1
Title Primary Pharmacodynamics
140 Element m4-2-1-1-primary-pharmacodynamics
Directory m4/42-stud-rep/421-pharmacol/4211-prim-pd
Comment
141 Number
Title Study Report 1
Element m4-2-1-1-primary-pharmacodynamics
File m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-1.pdf
Page 4-27
This comment is applicable to all study reports in Module 4.
A single file can be provided for each study report document in Module 4. However, where the study report is large (e.g., a carcinogenicity
study) the applicant can choose to submit the report as more than one file. In this case the text portion of the report should be one file and
the appendices can be one or more files. In choosing the level of granularity for these reports, the applicant should consider that, when
relevant information is changed at any point in the product's life cycle, replacements of complete files should be provided.
Comment Where submission as a collection of multiple files is used it is recommended that a directory is created at the study report level and the
relevant files included within the directory.
It is possible to have the additional graphical file(s) inserted directly into the PDF file, thus making management of the file easier.
Alternatively, the applicant can choose to manage graphical files independently.
Individual studies and files do not have specific CTD numbers.

Number
Comment
Number
Comment
Number 4.2.1.2
Title Secondary Pharmacodynamics
144 Element m4-2-1-2-secondary-pharmacodynamics
Directory m4/42-stud-rep/421-pharmacol/4212-sec-pd
Comment
Number
File m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-1.pdf
Comment
146 Number
Page 4-28
Element m4-2-1-2-secondary-pharmacodynamics
Comment
Number
Comment
Number 4.2.1.3
Title Safety Pharmacology
148 Element m4-2-1-3-safety-pharmacology
Directory m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol
Comment
Number
File m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-1.pdf
Comment
Number
Comment
Number
Comment
152 Number 4.2.1.4
Title Pharmacodynamic Drug Interactions
Element m4-2-1-4-pharmacodynamic-drug-interactions
Directory m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact
Page 4-29
Comment
Number
153 Element m4-2-1-4-pharmacodynamic-drug-interactions
File m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.2
Title Pharmacokinetics
156 Element m4-2-2-pharmacokinetics
Directory m4/42-stud-rep/422-pk
Comment
Number 4.2.2.1
Title Analytical Methods and Validation Reports (if separate reports are available)
157 Element m4-2-2-1-analytical-methods-and-validation-reports
Directory m4/42-stud-rep/422-pk/4221-analyt-met-val
Comment
Number
File m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-1.pdf
Comment
159 Number
Page 4-30
Element m4-2-2-1-analytical-methods-and-validation-reports
Comment
Number
Comment
Number 4.2.2.2
Title Absorption
161 Element m4-2-2-2-absorption
Directory m4/42-stud-rep/422-pk/4222-absorp
Comment
Number
File m4/42-stud-rep/422-pk/4222-absorp/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.2.3
Title Distribution
165 Element m4-2-2-3-distribution
Directory m4/42-stud-rep/422-pk/4223-distrib
Comment
Page 4-31
Number
File m4/42-stud-rep/422-pk/4223-distrib/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.2.4
Title Metabolism
169 Element m4-2-2-4-metabolism
Directory m4/42-stud-rep/422-pk/4224-metab
Comment
Number
File m4/42-stud-rep/422-pk/4224-metab/study-report-1.pdf
Comment
Number
Comment
172 Number
Element m4-2-2-4-metabolism
Page 4-32
Comment
Number 4.2.2.5
Title Excretion
173 Element m4-2-2-5-excretion
Directory m4/42-stud-rep/422-pk/4225-excr
Comment
Number
File m4/42-stud-rep/422-pk/4225-excr/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.2.6
Title Pharmacokinetic Drug Interactions (nonclinical)
177 Element m4-2-2-6-pharmacokinetic-drug-interactions
Directory m4/42-stud-rep/422-pk/4226-pk-drug-interact
Comment
Number
File m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-1.pdf
Comment
179 Number
Page 4-33
Element m4-2-2-6-pharmacokinetic-drug-interactions
Comment
Number
Comment
Number 4.2.2.7
Title Other Pharmacokinetic Studies
181 Element m4-2-2-7-other-pharmacokinetic-studies
Directory m4/42-stud-rep/422-pk/4227-other-pk-stud
Comment
Number
File m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-1.pdf
Comment
Number
Comment
Number
Comment
185 Number 4.2.3
Title Toxicology
Element m4-2-3-toxicology
Directory m4/42-stud-rep/423-tox
Page 4-34
Comment
Number 4.2.3.1
Title Single-Dose Toxicity (in order by species, by route)
186 Element m4-2-3-1-single-dose-toxicity
Directory m4/42-stud-rep/423-tox/4231-single-dose-tox
Comment
Number
File m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.2
Title Repeat-Dose Toxicity (in order by species, by route, by duration, including supportive toxicokinetics evaluations)
190 Element m4-2-3-2-repeat-dose-toxicity
Directory m4/42-stud-rep/423-tox/4232-repeat-dose-tox
Comment
Number
File m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-1.pdf
Comment
192 Number
Page 4-35
Element m4-2-3-2-repeat-dose-toxicity
Comment
Number
Comment
Number 4.2.3.3
Title Genotoxicity
194 Element m4-2-3-3-genotoxicity
Directory m4/42-stud-rep/423-tox/4233-genotox
Comment
Number 4.2.3.3.1
Title In vitro
195 Element m4-2-3-3-1-in-vitro
Directory m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro
Comment
Number
File m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Page 4-36
Number 4.2.3.3.2
Title In vivo (including supportive toxicokinetics evaluations)
199 Element m4-2-3-3-2-in-vivo
Directory m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo
Comment
Number
File m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.4
Title Carcinogenicity (including supportive toxicokinetics evaluations)
203 Element m4-2-3-4-carcinogenicity
Directory m4/42-stud-rep/423-tox/4234-carcigen
Comment
Number 4.2.3.4.1
Long-term studies (in order by species, including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
Title
pharmacokinetics)
204
Element m4-2-3-4-1-long-term-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud
Comment
205 Number
Page 4-37
Element m4-2-3-4-1-long-term-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-1.pdf
Comment
Number
206 Element m4-2-3-4-1-long-term-studies
Comment
Number
207 Element m4-2-3-4-1-long-term-studies
Comment
Number 4.2.3.4.2
Short- or medium-term studies (including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
Title
pharmacokinetics)
208
Element m4-2-3-4-2-short-or-medium-term-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud
Comment
Number
209 Element m4-2-3-4-2-short-or-medium-term-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-1.pdf
Comment
Number
210 Element m4-2-3-4-2-short-or-medium-term-studies
Comment
211 Number
Element m4-2-3-4-2-short-or-medium-term-studies
Page 4-38
Comment
Number 4.2.3.4.3
Title Other studies
212 Element m4-2-3-4-3-other-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud
Comment
Number
File m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.5
Reproductive and Developmental Toxicity (including range-finding studies and supportive toxicokinetics evaluations) (If modified study
Title
designs are used, the following subheadings should be modified accordingly)
216
Element m4-2-3-5-reproductive-and-developmental-toxicity
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox
Comment
Number 4.2.3.5.1
Title Fertility and early embryonic development
217 Element m4-2-3-5-1-fertility-and-early-embryonic-development
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev
Comment
218 Number
Page 4-39
Element m4-2-3-5-1-fertility-and-early-embryonic-development
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.5.2
Title Embryo-fetal development
221 Element m4-2-3-5-2-embryo-fetal-development
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev
Comment
Number
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-1.pdf
Comment
Number
Comment
224 Number
Element m4-2-3-5-2-embryo-fetal-development
Page 4-40
Comment
Number 4.2.3.5.3
Title Prenatal and postnatal development, including maternal function
225 Element m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev
Comment
Number
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.5.4
Title Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
229 Element m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv
Comment
Number
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-1.pdf
Comment
231 Number
Page 4-41
Element m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
Comment
Number
Comment
Number 4.2.3.6
Title Local Tolerance
233 Element m4-2-3-6-local-tolerance
Directory m4/42-stud-rep/423-tox/4236-loc-tol
Comment
Number
File m4/42-stud-rep/423-tox/4236-loc-tol/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.7
Title Other Toxicity Studies (if available)
237 Element m4-2-3-7-other-toxicity-studies
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud
Comment
Page 4-42
Number 4.2.3.7.1
Title Antigenicity
238 Element m4-2-3-7-1-antigenicity
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen
Comment
Number
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.7.2
Title Immunotoxicity
242 Element m4-2-3-7-2-immunotoxicity
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox
Comment
Number
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-1.pdf
Comment
244 Number
Element m4-2-3-7-2-immunotoxicity
Page 4-43
Comment
Number
Comment
Number 4.2.3.7.3
Title Mechanistic studies (if not included elsewhere)
246 Element m4-2-3-7-3-mechanistic-studies
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud
Comment
Number
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.7.4
Title Dependence
250 Element m4-2-3-7-4-dependence
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep
Comment
251 Number
Page 4-44
Element m4-2-3-7-4-dependence
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.7.5
Title Metabolites
254 Element m4-2-3-7-5-metabolites
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab
Comment
Number
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-1.pdf
Comment
Number
Comment
257 Number
Element m4-2-3-7-5-metabolites
Page 4-45
Comment
Number 4.2.3.7.6
Title Impurities
258 Element m4-2-3-7-6-impurities
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp
Comment
Number
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-1.pdf
Comment
Number
Comment
Number
Comment
Number 4.2.3.7.7
Title Other
262 Element m4-2-3-7-7-other
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other
Comment
Number
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-1.pdf
Comment
264 Number
Page 4-46
Element m4-2-3-7-7-other
Comment
Number
Comment
Number 4.3
Comment Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference).
Number
Title Reference 1
Comment
Number
Title Reference 2
Comment
Number
Title Reference 3
Comment
Page 4-47
Number 5
Title Clinical Study Reports
270 Element m5-clinical-study-reports
Directory m5
Comment
Number 5.2
Title Tabular Listing of all Clinical Studies
271 Element m5-2-tabular-listing-of-all-clinical-studies
Directory m5/52-tab-list
Comment
Number 5.2
Title Tabular Listing of all Clinical Studies
272 Element m5-2-tabular-listing-of-all-clinical-studies
File m5/52-tab-list/tabular-listing.pdf
Comment
Number 5.3
Title Clinical Study Reports
273 Element m5-3-clinical-study-reports
Directory m5/53-clin-stud-rep
Comment
Number 5.3.1
Title Reports of Biopharmaceutic Studies
274 Element m5-3-1-reports-of-biopharmaceutic-studies
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud
Comment
Number 5.3.1.1
Title Bioavailability (BA) Study Reports
275 Element m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep
Comment
276 Number
Page 4-48
Element m5-3-1-1-bioavailability-study-reports
Directory
m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-1
This comment is applicable to all study reports in Module 5.
The applicants should ordinarily provide the study reports as multiple files (a synopsis, a main body and appropriate appendices).
Appendices should be organized in accordance with the ICH E3 guideline, which describes the content and format of the clinical study
report. In choosing the level of granularity for reports the applicant should consider that, when relevant information is changed at any point
Comment
in the product's life cycle, replacements of complete files should be provided. A directory should be created for each study and the files
associated with the study report should be organized within the directory.
Individual studies and files do not have specific CTD numbers.

Number
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-2
Comment
Number
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-3
Comment
Number 5.3.1.2
Title Comparative BA and Bioequivalence (BE) Study Reports
279 Element m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep/study-report-1
Comment
281 Number
Element m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Page 4-49
Comment
Number
Comment
Number 5.3.1.3
Title In vitro – In vivo Correlation Study Reports
283 Element m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep/study-report-1
Comment
Number
Comment
Number
Comment
Number 5.3.1.4
Title Reports of Bioanalytical and Analytical Methods for Human Studies
287 Element m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met
Comment
288 Number
Page 4-50
Element m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met/study-report-1
Comment
Number
Comment
Number
Comment
Number 5.3.2
Title Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
291 Element m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat
Comment
Number 5.3.2.1
Title Plasma Protein Binding Study Reports
292 Element m5-3-2-1-plasma-protein-binding-study-reports
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep/study-report-1
Comment
Number
Comment
Page 4-51
Number
Comment
Number 5.3.2.2
Title Reports of Hepatic Metabolism and Drug Interaction Studies
296 Element m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud
Comment
Number
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud/study-report-1
Comment
Number
Comment
Number
Comment
Number 5.3.2.3
Title Reports of Studies Using Other Human Biomaterials
300 Element m5-3-2-3-reports-of-studies-using-other-human-biomaterials
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat
Comment
301 Number
Element m5-3-2-3-reports-of-studies-using-other-human-biomaterials
Page 4-52
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-1
Comment
Number
Comment
Number
Comment
Number 5.3.3
Title Reports of Human Pharmacokinetic (PK) Studies
304 Element m5-3-3-reports-of-human-pharmacokinetics-pk-studies
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud
Comment
Number 5.3.3.1
Title Healthy Subject PK and Initial Tolerability Study Reports
305 Element m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep/study-report-1
Comment
Number
Comment
308 Number
Page 4-53
Element m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
Comment
Number 5.3.3.2
Title Patient PK and Initial Tolerability Study Reports
309 Element m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep/study-report-1
Comment
Number
Comment
Number
Comment
Number 5.3.3.3
Title Intrinsic Factor PK Study Reports
313 Element m5-3-3-3-intrinsic-factor-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep
Comment
314 Number
Element m5-3-3-3-intrinsic-factor-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-1
Page 4-54
Comment
Number
Comment
Number
Comment
Number 5.3.3.4
Title Extrinsic Factor PK Study Reports
317 Element m5-3-3-4-extrinsic-factor-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep/study-report-1
Comment
Number
Comment
Number
Comment
321 Number 5.3.3.5
Title Population PK Study Reports
Page 4-55
Element m5-3-3-5-population-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep
Comment
Number
322 Element m5-3-3-5-population-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep/study-report-1
Comment
Number
Comment
Number
Comment
Number 5.3.4
Title Reports of Human Pharmacodynamic (PD) Studies
325 Element m5-3-4-reports-of-human-pharmacodynamics-pd-studies
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud
Comment
Number 5.3.4.1
Title Healthy Subject PD and PK/PD Study Reports
326 Element m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep/study-report-1
Comment
Page 4-56
Number
Comment
Number
Comment
Number 5.3.4.2
Title Patient PD and PK/PD Study Reports
330 Element m5-3-4-2-patient-pd-and-pk-pd-study-reports
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep/study-report-1
Comment
Number
Comment
Number
Comment
334 Number 5.3.5
Title Reports of Efficacy and Safety Studies
Element m5-3-5-reports-of-efficacy-and-safety-studies
Page 4-57
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud
Comment
Number 5.3.5
Title Reports of Efficacy and Safety Studies - Indication Name
Element m5-3-5-reports-of-efficacy-and-safety-studies
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1
The folder name should always include the indication being claimed, for example, 'asthma' (abbreviated if appropriate). Where there is
more than one indication (e.g., asthma and migraine), then the first indication has a folder 'asthma' and the second 'migraine'.
335
The ‘indication’ attribute in the backbone should be consistent with that used in the folder name but can be different. For example, an
Comment ‘indication’ attribute value of ‘Non-Small Cell Lung Cancer’ could be expressed as ‘NSCLC’ in the folder name. There is currently no
standard terminology list for ‘indication’ and applicants should choose the ‘indication’ attributes carefully as they can not be easily changed
during the life cycle of the application. The only way this can be accomplished currently is to delete all the leaf elements with the incorrect
attribute value and provide new leaf elements for those files with the modified attribute value. Applicants should consult with the regional
authority before attempting to modify these attributes to discuss the appropriateness of, and approach to be taken for, this type of change.
Number 5.3.5.1
Title Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
336 Element m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr
Comment
Number
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-1
Comment
Number
Comment
339 Number
Element m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
Page 4-58
Comment
Number 5.3.5.2
Title Study Reports of Uncontrolled Clinical Studies
340 Element m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr
Comment
Number
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr/study-report-1
Comment
Number
Comment
Number
Comment
Number 5.3.5.3
Title Reports of Analyses of Data from More than One Study
344 Element m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud
Comment
Number
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud/study-report-1
Comment
346 Number
Page 4-59
Element m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
Comment
Number
Comment
Number 5.3.5.4
Title Other Study Reports
348 Element m5-3-5-4-other-study-reports
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep
Comment
Number
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep/study-report-1
Comment
Number
Comment
Number
Comment
Number 5.3.6
Title Reports of Postmarketing Experience
352 Element m5-3-6-reports-of-postmarketing-experience
Directory m5/53-clin-stud-rep/536-postmark-exp
Comment
Page 4-60
Number 5.3.7
Title Case Report Forms and Individual Patient Listings
353 Element m5-3-7-case-report-forms-and-individual-patient-listings
Directory m5/53-clin-stud-rep/537-crf-ipl
Comment
Number
Title Study 1
Directory m5/53-clin-stud-rep/537-crf-ipl/study-1
Comment
Number
Title Document/Dataset 1
Element m5-3-7-case-report-forms-and-individual-patient-listings
355
File m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-1.pdf
The filename and extension should include the description of the file and appropriate file extension according to Appendix 2. Reference
Comment
should be made to regional guidance for the acceptability of submission of datasets
Number
Comment
Number
Comment
Number
Title Study 2
Comment define element
359 Number
Page 4-61
Element m5-3-7-case-report-forms-and-individual-patient-listings
Comment
Number
Comment
Number
Comment
Number
Title Study 3
Comment define element
Number
Comment
Number
Comment
Number
Comment
Page 4-62
Number 5.4
Comment Copies of literature references should ordinarily be submitted as individual files (i.e,. one for each reference).
Number
Title Reference 1
Comment
Number
Title Reference 2
Comment
Number
Title Reference 3
Comment
Page 4-63
Number
Title
370 Element
Directory util
Comment utilities
Number
Title
Element
371 Directory util/dtd
DTDs/Schemas – it is not necessary to include regional DTDs/Schemas other than the one for the region to which the application is being
Comment made.
File names in rows 372 - 379 are illustrative only. Please consult regional guidance for the current name and version of the files.
Number
Title
372 Element
File util/dtd/ich-ectd-n.dtd
Comment DTD for the instance – the version used to create the eCTD submission must be included. “n” denotes the specific version (e.g., 3-2).
Number
Title
373 Element
File util/dtd/eu-regional-n.dtd
Comment DTD for the EU specific documentation. “n” denotes the specific version (e.g., 1-1).
Number
Title
374 Element
File util/dtd/jp-regional-n.xsd
Comment Schema for the Japan specific documentation. “n” denotes the specific version (e.g., 1-0).
Number
Title
375 Element
File util/dtd/us-regional-n.dtd
Comment DTD for the US specific documentation. “n” denotes the specific version (e.g., 1-0).
Page 4-64
Number
Title
Element
376
File util/dtd/xx-regional-n.dtd
DTD for the xx specific documentation, where xx is a two character country code from ISO-3166-1. “n” denotes the specific version (e.g.,
Comment
1-0).
Number
Title
377 Element
Directory util/style
Comment Directory for style sheets – ICH and regional stylesheets
Number
Title
Element
378
File util/style/ectd-n.xsl
The specific version of the eCTD stylesheet used by the applicant as a reference during the creation of the submission should be included.
Comment
“n” denotes the specific version (e.g., 1-0).
Number
Title
Element
379
File util/style/xx-regional-n.xsl
Stylesheet for the xx specific documentation, where xx is a two character country code from ISO-3166-1. “n” denotes the specific version
Comment
(e.g., 1-0).
Page 4-65
Appendix 5: Region Specific Information Including Transmission and
Receipt
Introduction
This section describes region specific information for content that is not explicitly included in the Common
Technical Document and logistical details appropriate for the transmission and receipt of submissions using
the electronic Common Technical Document.
Region Specific Information: Module 1

This module contains administrative information that is unique for each region. There will be local
requirements for both the content and electronic component of module 1. The eCTD backbone was
developed to enable the transfer of the regional information included in a regulatory dossier.
Regional guidance will provide the specific instructions on how to provide the administrative forms and
detailed prescribing information. Please refer to this information and appendix 6 when preparing module 1.
Module 1 includes all administrative documents (e.g., forms and certifications) and labeling, including the
documents described in regional guidance.
Not all regionally specific documents are included in module 1. Technical reports required for a specific
region should be placed in modules 2 to 5. These reports should be included in the module most appropriate
for the content of the information provided.
Each region provides specific guidance on the format and content of the regional requirements of each
module. Table 5-1 provides contact information for each region.
Table 5-1
Region Internet Address Electronic Mail Contact
European Union http://www.emea.europa.eu [email protected]
Food And Drug Administration, www.fda.gov/cber [email protected]
USA www.fda.gov/cder [email protected]
Ministry of Health, Labour and http://www.mhlw.go.jp [email protected]

Welfare, Japan http://www.pmda.go.jp
Health Canada http://www.hc-sc.gc.ca [email protected]
Submission Addresses
Submissions should be sent directly to the appropriate regulatory authority. Information on how to send
submissions to each regulatory authority can be found at the reference location in Table 5-2.
Table 5-2
Regulatory Authority Reference location
EMEA, European Union http://www.emea.europa.eu
or national agencies http://www.hma.eu/
Ministry of Health, Labour and Welfare, Japan http://www.mhlw.go.jp
http://www.pmda.go.jp
Food and Drug Administration, United States of http://www.fda.gov/
America
Health Canada, Health Protection Branch, Canada http://www.hc-sc.gc.ca
Page 5-1
Media
Refer to regional guidance for appropriate media types.
Cover Letter
Applicants should provide a cover letter as a PDF file (e.g., cover.pdf). A paper cover letter should also be
included with non-electronic portions of the submission (such as forms with signatures or seals, and
certifications). The cover letter should include:
• 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.
• 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.
Transport
Secure data exchange over the Internet is the recommended means for transporting submissions. However,
until the regulatory authorities can develop secure electronic gateways, submissions should continue to be
physically transported by courier or registered mail.
Security
An MD5 checksum should be included for each physical file in the eCTD. The checksum enables the
recipient to verify the integrity of each of the content files in the submission. Each leaf of the XML eCTD
instance contains the location and calculated checksum of each of the files.
A checksum of the XML eCTD instance should also be included. Applicants should name this checksum
file index-md5.txt and include it as a file in the same directory as the XML eCTD instance. Applicants
should print the contents of the index-md5.txt file and include the paper copy with the paper cover letter for
the submission. A separate file containing the checksum of the regional index file is unnecesary as that file
(and its MD5 checksum) is referenced by a leaf element in the index.xml file.
An applicant can provide the eCTD as an encrypted file in accordance with the ICH M2 Recommendation
4.1, if the regulatory body has implemented it. This solution enables the eCTD to be encrypted and
transferred over the Internet (if Internet receipt is implemented regionally) or to be encrypted on one of the
approved physical media standards. The purpose of encryption is to protect the privacy of the confidential
information and to ensure it is only available to the authorized receiver. Encryption is always appropriate
when the eCTD is sent via the Internet.
Encryption is not considered necessary if the information is sent using a physical media, although
encryption is an option. The applicant should assume all liability for the media until it is delivered to the
regulatory authority.
Applicants should not include any file level security settings or password protection for individual files in
the eCTD. Applicants should allow printing, changes to the document, selecting text and graphics, and
adding or changing notes and form fields. Internal security and access control processes in the regulatory
authority should maintain the integrity of the submitted files.
Page 5-2
Receipt
Upon arrival at the regulatory authority, the submission is archived according to local regulations. A read-
only copy of the submission is then made available to the review community in the regulatory authority.
This is typically done by placing the copy on a network server.
Acknowledgment
Each regulatory authority should acknowledge the receipt of the eCTD submission according to the policy
and procedure of the individual regulatory authority. Applicants should use the address in Table 5-1 to find
guidance regarding acknowledgments.
Page 5-3
Appendix 6: The eCTD XML Submission
Background
Many factors have influenced the design of the eCTD. Factors that have had a significant impact on the
design are listed below:
• The submissions should accommodate full regulatory dossiers, supplements, amendments, and
variations.
• The submissions should be able to accommodate regional requirements that are represented in
regional guidance documents, regulations, and statutes.
• The technology should be extensible so that as technology changes, the new electronic solutions
can be accommodated.
The eCTD is designed around the concept of a backbone. The backbone is similar to a container that holds
pointers (called leaf elements) to the files that are part of the submission. The backbone is based on an
XML Document Type Definition (DTD). There is a close relationship between the documents defined in
the CTD and the elements defined in the eCTD DTD. The leaf elements in the backbone will provide the
navigation links to the various files and information that make up the submission.
The file that is produced based on the XML eCTD DTD is the eCTD XML instance or XML backbone.
The XML backbone allows more than one leaf element to point to the same physical file. This should be
done with caution since managing the life cycle of that file can be more difficult for the regulatory
authority if there is more than one pointer to the file.
File Names and Directory Structure

Recipients of the eCTD should be able to directly navigate through the submission at the folder and file
level (i.e., without benefit of a customized end user application.) The structure of the eCTD and
instructions for how to create folder names facilitate this type of navigation.
In order to preserve the navigational linkages that can be present in the documents contained in the eCTD,
the directory structure will be preserved by the agencies. The navigational links should be relative links
within a module.
Specific folder and file names have been defined in appendix 4. The top level of the directory structure
will vary by region. The identification of the top-level folder uniquely identifies the application in a region.
Consult regional guidance for specific requirements on top-level folder naming conventions. The original
submission and subsequent amendments and variations should use the same top-level folder name.
Submissions should be differentiated by a subfolder named according to the sequence number of the
submission in that region. For all regions, sequence numbers should be unique within the overall
application. For Japanese submissions, sequential numbering is required. For all other regions, it is
preferred, but not required. Table 6-1 and Figure 6-1 illustrate this naming convention.
Table 6-1
Example top level folder name Sequence number Type of submission
ctd-123456 0000 Original Submission
ctd-123456 0001 First amendment, supplement or
variation
ctd-123456 0002 Second amendment, supplement
or variation
…
ctd-123456 Nnnn Nth amendment, supplement or
variation
Page 6-1
Figure 6-1
You should submit the XML backbone as a single file named index.xml, which should be placed in the
submission sequence number folder for that submission. In the example shown in Figure 6-1, there should
be an index.xml file in folder “0000”, folder “0001” and folder “0002”. The MD5 checksum file, index-
md5.txt, should be in each folder with the corresponding index.xml file. The DTD for index.xml should be
in the “util” folder for each submission.
The regional administrative XML backbone file should be in the region specific module 1 folder for each
submission. For each sequence, the operation attribute of the leaf element referencing this file is always
‘new’. A separate file containing the checksum of the regional index file is unnecessary as that file (and its
MD5 checksum) is referenced by the index.xml file. The DTD for the regional XML backbone file should
be in the util folder for each submission.
Table 6-2 presents the file locations for the example in Figure 6-1.
Table 6-2
Submission Folder Files
ctd-123456/0000 index.xml
index-md5.txt
ctd-123456/0000/m1/us us-regional.xml
ctd-123456/0000/util/dtd ich-ectd-3-x.dtd
us-regional-vx-x.dtd
index-md5.txt
index-md5.txt
Life Cycle Management

It is important for the recipients of an eCTD to be able to establish the location of the submission in the life
cycle of a product.
Page 6-2
The eCTD is capable of containing initial submissions, supplements, amendments, and variations. There
are no uniform definitions for these terms in the three regions, but amendments and supplements are terms
used in the United States. Variations apply in Europe. The variations, supplements, and amendments are
used to provide additional information to an original regulatory dossier. For example, if a new
manufacturer for the drug substance were being proposed, this would result in submission of an amendment
or supplement to the FDA and a variation to Europe. When regulatory authorities request additional
information, the information is also provided as a variation, supplement, or amendment to the original
submission. Therefore, the regulatory agencies need a way to manage the life cycle of the submission.
This function will be provided by each regulatory authority in the form of guidance that can include
regional DTDs and specifications. The relevant regional DTD should be referenced in the eCTD DTD by
the applicant.
The eCTD DTD provides some facilities for life cycle management at the leaf element level but does not
fully support the life cycle at the submission level. When revisions are sent to a regulatory authority, the
new leaf element should be submitted in the same location in the backbone as the leaf element being
appended, replaced or deleted. The “modified-file” attribute of the leaf element should contain the leaf ID
of the leaf being appended, replaced, or deleted. This will allow the regulatory authority to accurately
locate the original leaf and update the original leaf’s status. A detailed description of modified-file is
provided in the next section.
Operation Attribute
The operation attribute is a key to managing each individual leaf element in a submission. The applicant
uses the operation attribute to tell the regulatory authority how the applicant intends the leaf elements in the
submission to be used. The operation attribute describes the relation between leaf elements in subsequent
submissions during the life cycle of a medicinal product. In the very first submission all the leaf elements
would typically be new. In the second, third, and subsequent submissions, all the newly submitted leaf
elements can have different operation attributes due to having or not having a relation with previously
submitted leaf elements. Table 6-3 describes the meaning of each allowed value of the operation attribute.
Table 6-3: Understanding the Operation Attribute
What the reviewer might see

Operation when using the Agency review
attribute software
value Meaning This leaf Previous leaf
New The leaf element has no relationship with leaf elements Current
submitted previously. It is acceptable for multiple leaf
elements in a single eCTD element to have the operation
attribute of new, either in the same sequence or during
the life cycle of the application.
Append This means there is an existing leaf element to which Current Current -
this new leaf element should be associated. (e.g., Appended
providing missing or new information to that leaf
element). It is recommended that append not be used to
associate two leaf elements in the same submission (e.g.,
splitting a file due to size restrictions). However, use of
append could be appropriate when leaf elements which
normally would be submitted with the append
relationship are provided in the same sequence (e.g., a
document and its amendment). Consult with the
regulatory authority before using append to associate
two leaf elements in the same sequence.
Replace This means there is an existing leaf element that this Current Replaced
Page 6-3
What the reviewer might see
Operation when using the Agency review
attribute software
value Meaning This leaf Previous leaf
new leaf element replaces.
Delete There is no new file submitted in this case. Instead, the No longer
leaf element has the operation of “delete” and the relevant to the
“modified-file” attribute identifies the leaf element in a review
previous submission that is to be considered no longer
relevant to the review. As there is no file being
submitted, the checksum attribute value will be empty
i.e., double quotation marks with no entry between (“”).
The purpose of the modified-file attribute is to provide the location of a leaf element that is being modified
(i.e. replaced, appended or deleted) by the subsequent leaf element. The modified-file attribute should have
a value when the operation attribute has a value of append, replace or delete. The modified-file attribute
points to the “index.xml” file and the leaf ID of the leaf element being altered. The modified-file attribute
can only target a single leaf element. Furthermore, once a leaf element has been replaced or deleted by
another leaf element, it is no longer current and can no longer be targeted by any subsequent leaf elements
through the modified-file attribute.
An example of a modified-file attribute value is provided below:
modified-file="../0001/index.xml#a1234567"
This would provide the information needed to locate the file with the leaf element ID assigned as
"a1234567" and provided in the sequence folder numbered "0001".
If a modified-file attribute is presented with no value (i.e. no characters or spaces between the quotation
marks, modified-file="") it will be the same as not including the attribute in the leaf element.
The following case examples show the use of each of the operation attribute values. These examples do not
cover all possible situations. Consult the appropriate regulatory authority if you have specific questions
about the use of the operation attribute. When actually populating the XML instance, use the leaf ID to
refer to files.
Case 1 – The first submission of a dossier.

Table 6-4
Submission File name Operation File Being Sample logical display
sequence # Modified in a review tool
0000 0000\…\structure.pdf New structure.pdf (current)
Case 2 – Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is a
subsequent amendment or variation in which the applicant intends to completely replace the structure.pdf
file in submission 0000. The intent is to keep the original structure.pdf for historical purposes but to
consider only the contents of the 0001\…\structure2.pdf as relevant to the review. These two submissions
could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf, and this file is the current
version of this file.
- Submission 0001, which is submitted at a later time, is the submission of the file
structure2.pdf, which is now current and replaces the file structure.pdf in submission 0000.
There is no requirement to preserve file names during life cycle changes; in fact, logical differences in file
names can be helpful during review when both files are open simultaneously for comparative or other
purposes.
Page 6-4
Table 6-5
Submission File name Operation File Being Modified Sample logical display
sequence # in a review tool
0001 0001\…\structure2.pdf Replace 0000\…\structure.pdf structure.pdf (replaced)
structure2.pdf (current)
Case 3 – Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is an
amendment or variation where the applicant intends to add new information to the original structure.pdf
file, which was submitted in submission 0000. The intent is to have the reviewer consider the contents of
both files relevant to the submission. These two submissions could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf, and this file is the current
- Submission 0001, submitted at a later time, is the submission of the file structure2.pdf, which
is the current file but contains information that should be appended to file structure.pdf in
submission 0000. Both files should be considered relevant to the review of the dossier.
There is no requirement to preserve file names during life cycle changes; in fact, logical differences in file
names can be helpful during review when both files are open simultaneously for comparative or other
purposes.
Table 6-6
Submission File name Operation File Being Modified Sample logical display
sequence # in a review tool
0001 0001\…\structure2.pdf Append 0000\...\structure.pdf structure.pdf (current -
appended)
structure2.pdf (current)
Case 4 – Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is an
amendment or variation where the applicant intends to delete a file in the previous submission. The intent
is to have the reviewer disregard the contents of the original file, possibly because it should not have been
submitted with the original dossier. These two submissions could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf and this file is the current
- Submission 0001, submitted at a later time, requests that the file structure.pdf in submission
0000 be deleted and no longer considered relevant to the review of the dossier.
Table 6-7
Submission File name Operation File Being Sample logical display in
sequence # Modified a review tool
0000 0000\...\structure.pdf New structure.pdf (current)
0001 Delete 0000\...\structure.pdf structure.pdf (no longer
relevant to the review)
File Reuse
It is important to the successful utilization of the eCTD to clearly understand the differences between a file
and a leaf element. When reviewing an eCTD sequence, either through the stylesheet or an eCTD viewing
tool, the presentation of the organization of the content files is based on the organization of the leaf
elements in the index.xml files. The underlying file and folder structure is not critical to the view of the
organization of the files referenced in the XML backbone. This aspect of the eCTD provides users the
ability to provide a file once and display it in multiple locations of the eCTD by providing multiple leaf
Page 6-5
elements referencing that file. Users of the eCTD Specification are encouraged to provide files once in a
sequence and provide as many leaf elements referencing that file as necessary. The location of the file is
not critical and should only be included once in an appropriate place in the folder structure. Suppliers of
eCTD viewing tools are encouraged to develop a visual way of displaying when this occurs so reviewers
can readily identify files which are referenced multiple times.
This capability can also be extended across sequences and even applications as long as the location of the
file is accurately cited in the xlink:href attribute for the leaf element referencing that file. Suppliers of
eCTD viewing tools are encouraged to develop a visual way of displaying the difference between a leaf
element referring to a file in the current sequence and a leaf element referring to a file in a previous
sequence. In these situations, validation checks for the presence of files referenced by the XML backbone
should allow for the xlink:href to refer to files in other sequences and not prevent viewing of the eCTD by
another applicant/regulator. Users of the eCTD Specification should consult with the regulatory authority
before referencing content across sequences and/or applications.
DTD Content Model

The content model of the eCTD is derived from the organization of the Common Technical Document.
The graphic representation of a portion of the content model is shown below. The content model is
hierarchical starting at the “ectd” and going down to a specific item to be included in the submission.
Figure 6-2
Page 6-6
Figure 6-3 shows how the section of the CTD containing summaries is structured.
Figure 6-3
Once the appropriate element has been selected (e.g., Figure 6-4), you should use the <leaf> element and
attributes (Figure 6-5) to specify a file in the submission. See “eCTD Element/Attribute Instructions” in
this appendix for details.
Figure 6-4
Page 6-7
Figure 6-5
eCTD Element/Attribute Instructions

The eCTD consists of 5 primary modules:
• m1-administrative-information-and-prescribing-information
• m2-common-technical-document-summaries
• m3-quality
• m4-nonclinical-study-reports
• m5-clinical-study-reports
Each of the 5 modules is divided into one or more elements, each with a distinct element identifier that
represents a CTD table of contents location. The steps should be completed as shown in the following
example, where all files are submitted for modules 1 through 5:
1. Select an element that best corresponds to the CTD table of contents location for a document or file
being submitted. For example, select the element <m2-7-3-summary-of-clinical-efficacy> to submit
the summary of clinical efficacy document.
2. Specify any additional element attribute as appropriate; in this example, specify the ‘indication’
attribute to identify the subject of the efficacy summary in 2.7.3.
3. Create a child <leaf> element within the <m2-7-3-summary-of-clinical-efficacy> element.
4. Provide the relative location and file name of the actual file in the “xlink:href” attribute for the leaf
element.
5. Provide a descriptive and concise title for the file in the <title> element of the leaf element.
6. Provide information for the appropriate attributes of the leaf element as described in Table 6-8.
Table 6-8 describes each of these elements and attributes in further detail.
Page 6-8
Table 6-8
Element Attribute Description/Instructions Example
Any table of A table of contents element
contents represents a grouping of one or more
element such files related to a specific section of
as <m2-4- the Common Technical Document. A
nonclinical- number of TOC elements can be
overview> further defined by the use of
attributes. The eCTD DTD defines
the following attributes at various
places in the eCTD: substance,
manufacturer, product-name,
indication, excipient, dosage-form
(e.g., 2.3.S and 3.2.S have two ‘free
text’ attributes: substance and
manufacturer; 5.3.5 has the
additional ‘free text’ attribute,
indication). To be consistent with the
CTD General Q&A, values for these
attributes should be included where
specified as is appropriate. There is
currently no standard terminology list
for any of these attributes and
applicants should carefully choose
the text of these attributes as they can
not be easily changed during the life
cycle of the application.
One or more child <leaf> elements
can be declared for a parent table of
contents element.
It is possible to extend a table of
contents element by providing a
<node-extension> element. Node
extensions should only be added at
the lowest level of the defined table
of contents elements. Using node
extensions is discouraged and should
be done only when unavoidable.
Please refer to regional guidance
before using node extensions. See
the section “Instructions for
extending XML eCTD DTD
elements” in this appendix (Example
6-5).
ID A unique identifier for this location id403 (note: At this level, ID is optional)
in the XML instance.
xml:lang The primary language used by the en
files in this entire section of the
submission. Use ISO-639 standard
language abbreviations
Page 6-9
<leaf> A leaf element is a reference to a file.
One or more leaf elements can be
declared for a table of contents
element.
application- This is the version of the file format PDF 1.4

version produced by the software application
that was used to create this file.
font-library Reserved for Future Use
ID The ID attribute is intended to be a id050520

unique reference within the NOTE: See the XML-ID
submission that can be used to recommendations on the W3C website for
reference the item from another item info on the composition of this attribute
within the XML document. An value (http://www.w3.org/TR/xml-
XML ID value begins with an id/#processing)
alphabetic character or underscore.
If an applicant is using an internal ID
generator that uses only numbers,
appending this generated number to a
leading alphabetic character or
underscore will create a valid ID
value.
checksum The checksum value for the file e854d3002c02a61fe5cbe926fd97b001
being submitted.
checksum- The checksum algorithm used. MD5
type
modified- The purpose of the modified-file ../0001/index.xml#a1234567
file attribute is to provide the location of
the leaf that is being modified (i.e.
replaced, appended or deleted) by the
leaf element. The modified-file
attribute should have a value when
the operation attribute has a value of
append, replace or delete. The
modified-file attribute points to the
“index.xml” file and the leaf ID of
the leaf being altered.
operation Indicates the action to be performed. new
You should select one of the
following valid values:
• new
• replace
• append
• delete
See the section Operation Attribute
in this appendix for details on the
meaning of these values.
version The file submitter’s internal version V23.5
number or version identification for
the file.
xlink:actuate Reserved for Future Use
Page 6-10
xlink:href Provides the reference to the actual 0000/m2/27-clin-sum/literature-
content file. You should use the references.pdf
relative path to the file and the file
name. The content file does not need
to be in the same sequence as the leaf
element that refers to it.
xlink:role Reserved for Future Use
xlink:show Reserved for Future Use
xlink:type Fixed value of “simple” simple
keywords Reserved for Future Use
<title> As part of the leaf element, this Study Report 1234
element contains a practical name for NOTE: Leaf titles should be concise;
the file being referenced by the leaf. 1024 bytes (512 characters) are proposed
as the maximum length
ID Unique identifier for this location in a1234567
the XML instance. Leaf ID starts NOTE 1: See the XML-ID
with an alphabetic character or recommendations on the W3C website for
underscore. info on the composition of this attribute
value (http://www.w3.org/TR/xml-
id/#processing)
NOTE 2: At this level, ID is optional
<link-text> Reserved for Future Use

<xref> Reserved for Future Use
Example 6-1: Instructions for a Simple New Submission 7

The following XML fragment demonstrates the submission of a clinical overview of efficacy as a single
PDF document.
<?xml version = "1.0" encoding = "UTF-8"?>

<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-x.dtd">
<?xml-stylesheet type="text/xsl" href="util/style/ectd-2-1-x.xsl"?>
<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<m2-common-technical-document-summaries>
<m2-5-clinical-overview xml:lang = "en">
<leaf ID="s123456" operation = "new" xlink:type = "simple" checksum-type=“md5”
checksum = "e854d3002c02a61fe5cbe926fd973401" xlink:href = "m2/25-clin-
over/clinical-overview.pdf" application-version = "PDF 1.4">
<title>Clinical Overview</title>
</leaf>
</m2-5-clinical-overview>
</m2-common-technical-document-summaries>
</ectd:ectd>
This submission includes the file “clinical-overview.pdf” in the relative directory “m2/25-clin-over/” (i.e.
the one starting below the dossier number directory). The file is “new” and has a descriptive name of
“Clinical Overview”
The regional review application should treat this as a new submission to be associated with the submission
identified in CTD module 1, which is region specific.
7
Note that these XML examples are examples only and do not necessarily contain all of the elements and
attributes that you should use when preparing an eCTD submission.
Page 6-11
If this is the first submission for Dossier CTD 123456, all the files in this submission would typically be in
the ctd-123456\0000 directory and below.
Example 6-2: Instructions for an Amendment, Supplement, or

Variation
In the previous example, a clinical overview was submitted. In this example, it is replaced by an updated
version.
To replace a file, add the replacement <leaf> element under the same element as the original file.
If this is the second submission for Dossier CTD 123456, all the files in this submission would typically be
in the ctd-123456\0001 directory and below.

<leaf ID=“a123457” operation = "replace" xlink:type = "simple" checksum-type="md5" checksum =
"502e9ab5827431f077340cea3b5e465a" xlink:href = "m2/25-clin-over/clinical-overview-revised.pdf"
application-version = "PDF 1.4" modified-file = "../0000/index.xml#s123456">
<title>Clinical Overview</title>
</leaf>
</ectd:ectd>
Example 6-3: Instructions for Multiple Indications

Multiple therapeutic indications use an additional attribute associated with the <m2-7-3-summary-of-
clinical-efficacy> and the <m5-3-5-reports-of-efficacy-and-safety-studies> elements to allow multiple
indications to be submitted. There is currently no standard terminology list for ‘indication’. Applicants
should choose these attributes carefully as they can not be easily changed during the life cycle of the
application. The only way this can be accomplished currently is to delete all the leaf elements with the
incorrect attribute value and provide new leaf elements for those files with the modified attribute value.
Applicants should consult with the regional authority before attempting to modify these attributes to
discuss the appropriateness of, and approach to be taken for, this type of change. The following table shows
the use of these attributes.
Table 6-9
<m2-7-3-summary-of-clinical-efficacy> indication Name of the indication Pain
<m5-3-5-reports-of-efficacy-and-safety- indication Name of the indication. Pain
studies>
Note that the indication attribute is used by the regulatory authority to apply to all the table of contents
elements beneath the <m2-7-3-summary-of-clinical-efficacy> and <m5-3-5-reports-of-efficacy-and-safety-
studies> elements. The following example expands on the instance showing the submission of information
about two indications (pain and nausea).

Page 6-12
<m2-7-clinical-summary>
<m2-7-3-summary-of-clinical-efficacy indication = "pain">
<leaf ID=“s123456“operation = "new" xlink:type = "simple" checksum-type=“md5“ checksum =
"5aa5c0e630a700af869e4c72535fc922" xlink:href = "m2/27-clin-sum/summary-clin-efficacy-
pain.pdf">
<title>pain efficacy summary</title>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>
<m2-7-3-summary-of-clinical-efficacy indication = "nausea">
<leaf ID=“a123457“ operation = "new" xlink:type = "simple" checksum-type=“md5“ checksum =
"bde4d34dc80678a266352daf450c3962" xlink:href = "m2/27-clin-summ/summary-clin-efficacy-
nausea.pdf">
<title>nausea efficacy summary</title>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>
</m2-7-clinical-summary>
<m5-clinical-study-reports>
<m5-3-clinical-study-reports>
<m5-3-5-reports-of-efficacy-and-safety-studies indication = "pain">
<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication>
<leaf ID=“a123458“ operation = "new" xlink:type = "simple" checksum-type=“md5" checksum =
"a4529c4a257f07f8a0ec591dde854578" xlink:href = "m5/53-clin-stud-rep/535-rep-eff-safety-
stud/pain/pain-sr1.pdf">
<title>pain study report 1</title>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication>
</m5-3-5-reports-of-efficacy-and-safety-studies>
<m5-3-5-reports-of-efficacy-and-safety-studies indication = "nausea">
<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication>
<leaf ID=“a123459“ operation = "new" xlink:type = "simple" checksum-type=“md5“ checksum =
"c5c39f594b2070a57bea66e58860efcf" xlink:href = "m5/53-clin-stud-rep/535-rep-eff-safety-
stud/nausea/nausea-sr15.pdf" >
<title>nausea study report 15</title>
</leaf>
<leaf ID = "a123460" operation = "new" xlink:type = "simple" checksum-type = "md5" checksum
= "15faf198015f3599acabb7755c2d6b0c" xlink:href = "m5/53-clin-stud-rep/535-rep-eff-
safety-stud/nausea/5351-stud-rep-contr/xyz0015/nausea-sr15.pdf">
<title>nausea study report 15</title>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication>
</m5-3-5-reports-of-efficacy-and-safety-studies>
</m5-3-clinical-study-reports>
</m5-clinical-study-reports>
</ectd:ectd>
Example 6-4: Instructions for Multiple Drug Substances,

Manufacturers, and Products
Multiple drug substances use additional attributes associated with the <m3-2-s-drug-substance> element to
allow unique combinations of the drug substance name and manufacturer to be submitted. There are
currently no standard terminology lists for these attributes. Applicants should choose these attributes
carefully as they can not be easily changed during the life cycle of the application. The only way this can be
accomplished currently is to delete all the leaf elements with the incorrect attribute value and provide new
leaf elements for those files with the modified attribute value.Applicants should consult with the regional
authority before attempting to modify these attributes to discuss the appropriateness of, and approach to be
taken for, this type of change. The following table shows the use of these attributes in 3.2.S.
Page 6-13
Table 6-10
<m3-2-s-drug-substance> substance Name of one of the drug substances Acetaminophen
manufacturer Name of the manufacturer of the drug substance My Supplier
Example 6-4A:
This is an example of a section of the instance showing the submission of information about two drug
substances (acetominophen and codeine), one of which is supplied by two manufacturers:
<m3-2-body-of-data>
<m3-2-s-drug-substance substance = "Acetaminophen" manufacturer = "My Supplier">
<leaf ID=“a123456” operation = "new" xlink:type = "simple" checksum-type=“md5” checksum =
"b002e4544c02361fe54be926ae777012" xlink:href = "m3/32-body-data/32s-drug-
sub/acetaminophen-my-supplier/acetaminophen.pdf">
<title>Acetaminophen - My Supplier Data</title>
</leaf>
</m3-2-s-drug-substance>
<m3-2-s-drug-substance substance = "Acetaminophen" manufacturer = "Bulk Company 2">
"0000cdfa05b1e995f88057150414a783" xlink:href = "m3/32-body-data/32s-drug-
sub/acetaminophen-bulk-company-2/acetaminophen2.pdf">
<title>Acetaminophen - bulk company 2 data</title>
</leaf>
<m3-2-s-drug-substance substance = "Codeine" manufacturer = "Drug company 2">
"f555a3234f65623fe54be926ee435354" xlink:href = "m3/32-body-data/32s-drug-sub/codeine-
drug-company-2/codeine-quality-data.pdf">
<title>codeine - drug company 2 data</title>
</leaf>
</m3-2-body-of-data>
Multiple drug products use additional attributes associated with the <m3-2-p-drug-product> element to
allow unique combinations of the drug product name and dosage form to be submitted. Applicants should
choose these attributes carefully as they can not be easily changed during the life cycle of the application.
The only way this can be accomplished currently is to delete all the leaf elements with the incorrect
attribute value and provide new leaf elements for those files with the modified attribute value. Applicants
should consult with the regional authority before attempting to modify these attributes to discuss the
appropriateness of, and approach to be taken for, this type of change. The following table shows the use of
these attributes in 3.2.P.
Table 6-11
<m3-2-p-drug-product> product-name Name of one of the drug products Wonder drug
dosageform Dosage form Capsule
manufacturer Manufacturer of the drug product Company A
Example 6-4B
This is an example of a section of the instance showing the submission of information about two drug
products (a capsule and a tablet):
<m3-2-body-of-data>
<m3-2-p-drug-product product-name = “Wonder drug” dosageform=“Capsule” manufacturer=“Company
A”>
Page 6-14
"f27cd9e659d8acf7baab10cc753d733c" xlink:href = "m3/32-body-data/32p-drug-prod/capsule-
5mg/32p1-desc-comp/description-and-composition.pdf">
<title>Wonder drug capsule product information</title>
</leaf>
</m3-2-p-drug-product>
<m3-2-p-drug-product product-name = “Wonder drug” dosageform=“Tablet” manufacturer=“Company A”>
"7490d74c3d5e442ad57daa155253eb16" xlink:href = "m3/32-body-data/32p-drug-prod/tablet-
5mg/32p1-desc-comp/description-and-composition.pdf">
<title>Wonder drug tablet product data</title>
</leaf>
</m3-2-p-drug-product>
</m3-2-body-of-data>
Example 6-5: Instructions for Extending XML eCTD DTD Elements

An applicant can extend the definition of an element by creating node extensions beneath a defined table of
contents element. Using node extensions is discouraged and should be done only when unavoidable. Please
refer to regional guidance before using node extensions. The child element <node-extension> should be
used for each new table of contents node created. The <title> element value is inherited from the parent
element. You should only extend the lowest level of defined elements. For example you can extend the
<m2-3-r-regional-information> element but not the <m2-3-quality-overall-summary> element since the
latter is not the lowest element defined in the table of contents.
The following is an example of a section of an eCTD instance in which the applicant extends the <m2-3-r-
regional-information> to provide specific regional information as requested by a regulatory authority. The
title element associated with the <node-extension> describes the extension. Alternatively, the regional
information in this example could have been provided as a <leaf> element under the <m2-3-r-regional-
information> element without the use of a “node extension”.
<m2-3-quality-overall-summary>
<m2-3-r-regional-information>
<node-extension>
<title>special-summary</title>
<leaf ID=“a123456” operation = "new" xlink:type = "simple" xlink:href = "m2/23-qos/extra-
quality-sum.pdf" checksum-type=“md5” checksum = "7490d74c3d5e442ad57daa155253eb16">
<title>Extra Quality Summary </title>
</leaf>
</node-extension>
</m2-3-r-regional-information>
</m2-3-quality-overall-summary>
To update a file that has been submitted as an extended node, you should submit the replacement file using
exactly the same element and “node extension” information, including the <title> element for the <node-
extension>. This makes it possible for the regulatory authority to locate the original file and update its
status.
Example 6-6: Instructions for Submitting Sections as Paper

During the transition to fully electronic submissions of the CTD, some regions will accept that some
sections can be submitted as paper only. Please refer to regional guidance. These sections should be
identified in the XML eCTD instance by including a PDF file in the instance that describes the content and
location of the paper section. For example, the PDF file might consist of only one page with the name of
the CTD document and the physical volume number and tab identifier. The <title> element in the XML
eCTD instance could indicate that this is a paper submission.
Page 6-15
This is an example of the instance showing the submission of a paper efficacy overview document.
"e854d3002c02a61fe5cbe926fd973401" xlink:href = "m2/25-clin-over/clinical-overview.pdf" application-
version = "PDF 1.4">
<title>Paper Submission </title>
</leaf>
Page 6-16
Appendix 7: Specification for Submission Formats
Introduction
This appendix describes the way files should be constructed for inclusion in the eCTD. This section
includes file formats that are commonly used in electronic submissions. Other formats can be used
according to guidance published in each region.
PDF
Adobe Portable Document Format (PDF) is a published format created by Adobe Systems Incorporated
(http://www.adobe.com). It is not necessary to use a product from Adobe or from any specific company to
produce PDF documents. PDF is accepted as a standard for documents defined in this specification. The
following recommendations support the creation of PDF files that agencies can review effectively. For any
specification of the Japanese version of Adobe Acrobat, or where Japanese characters will be in the file,
please refer to the regional guidance.
To ensure that PDF files can be accessed efficiently, PDF files should be no larger than 100 megabytes.
Optimize PDF files for fast web view.
Version
All ICH Regional Health Authorities are able to read and have agreed to accept PDF files saved as PDF
version 1.4. Agencies should not need any additional software to read and navigate the PDF files. PDF/A-1
(an ISO standard - ISO 19005-1:2005) is an archive format and does not meet the ICH review needs for use
with an eCTD. Please consult regional guidance to submit other versions of PDF.
Fonts
PDF viewing software automatically substitutes a font to display text if the font used to create the text is
unavailable on the reviewer’s computer. Font substitution can affect a document’s appearance and
structure, and, in some cases, the information conveyed by a document. Agencies cannot guarantee the
availability of any fonts except Times New Roman, Arial, and Courier and fonts supported in the Acrobat
product set itself. Therefore, all additional fonts used in the PDF files should be embedded to ensure that
those fonts would always be available to the reviewer. When embedding fonts, all characters for the font
should be embedded, not just a subset of the fonts being used in the document
Embedding fonts requires additional computer storage space. Three techniques to help limit the storage
space taken by embedding fonts include:
• Limiting the number of fonts used in each document
• Using only True Type or Adobe Type 1 fonts
• Avoiding customized fonts
Japanese fonts (2-byte fonts) are larger than Roman fonts (1-byte fonts), therefore, the specification allows
a subset to be embedded for all Japanese fonts. The purpose of embedding fonts to is to enable the receiver
of the document to use a personal computer to display and print the document correctly without having the
same fonts installed in the computer. Therefore, it is not necessary to embed all Japanese fonts. Embedding
a subset of Japanese fonts should work satisfactorily.
Definition of Subset
A subset means to embed only those characters used in the document. Embedding a full-set means all
characters that comprise the font are embedded, even characters that are not used in the document. All
two-byte fonts such as Japanese should be embedded as a sub-set.
Page 7-1
Notes on Embedding Japanese Fonts:
The following should be considered when embedding fonts:
Advantages:
• Embedding fonts allows the PDF file to be correctly displayed and printed on any receiving PC
environment.
• The computer does not need the original fonts installed.
Disadvantages:
• The file size increases when fonts are embedded.
• When document contains many pages, this can make the document slower to print.
• Many eCTD documents contain a large number of pages. Printing time in such cases becomes a
concern.
• When using Japanese fonts, rules of operation should be established between the sender and receiver.
(See regional guidance)
• The use of popular fonts only would allow the sender and receiver to view and print the document
correctly without embedding fonts.
Font Size
Resizing a document because the contents are too small to read is inefficient. Times New Roman, 12-point
font, the font used for this document, is adequate in size for narrative text and should be used whenever
possible. It is sometimes tempting to use fonts which are smaller than 12 point in tables and charts but this
should be avoided whenever possible. When choosing a font size for tables, a balance should be sought
between providing sufficient information on a single page to facilitate data comparisons for the reviewer
while maintaining a font size that remains legible. The corollary of this is that in using larger font size,
more tables might be necessary, which can complicate data comparisons since data might now be included
in separate tables. Generally, Times New Roman font sizes 9-10 or an equivalent size of other
recommended fonts are considered acceptable in tables but smaller font sizes should be avoided.
Use of Color Fonts

The use of a black font color is recommended. Blue can be used for hypertext links. Light colors that do
not print well on grayscale printers should be avoided. Color reproduction can be tested prior to
submission by printing sample pages from the document using a gray scale printer. The use of background
shadowing should be avoided.
Page Orientation
Pages should be properly oriented so that all portrait pages are presented in portrait and all landscape pages
are presented in landscape. To achieve this, the page orientation of landscape pages should be set to
landscape prior to saving the PDF document in final form.
Page Size and Margins

The print area for pages should fit on a sheet of A4 (210 x 297 mm) and Letter (8.5” x 11”) paper. A
sufficient margin (at least 2.5 cm) on the left side of each page should be provided to avoid obscuring
information if the reviewer subsequently prints and binds the pages for temporary use. For pages in
landscape orientation (typically tables and publications), smaller margins (at least 2.0 cm at the top and 0.8
cm left and right) allow more information to be displayed legibly on the page (see Fonts). Header and
footer information can appear within these margins but should not appear so close to the page edge to risk
being lost upon printing.
Headers and Footers

The M4 Granularity document specifies that all pages of a document should include a unique header or
footer that briefly identifies its subject matter. With the eCTD there is a significant amount of metadata
Page 7-2
available to the reviewer to allow easy identification of the document but it is still appropriate to have a
unique identifier on each page (header or footer) of the document (e.g., when the document is printed or
multiple documents are viewed on screen at the same time). The unique identifier does not necessarily have
to contain the CTD section identifier or other metadata. It should be sufficient to identify the general
subject matter of the document (e.g., study identifier, batch number).
Source of Electronic Document

PDF documents produced by scanning paper documents are usually inferior to those produced from an
electronic source document. Scanned documents saved as image files are more difficult to read and do not
allow reviewers to search or copy and paste text for editing. Scanning should be avoided where possible.
Methods for Creating PDF Documents and Images

The method used for creating PDF documents should produce the best replication of a paper document. To
ensure that the paper and PDF version of the document are the same, the document should be printed from
the PDF version. Documents that are available only in paper should be scanned at resolutions that will
ensure the pages are legible both on the computer screen and when printed. At the same time, the file size
should be limited. It is recommended that scanning be undertaken at a resolution of 300 dots per inch (dpi)
to balance legibility and file size. The use of grayscale or color is discouraged because of file size. After
scanning, resampling to a lower resolution should be avoided.
When creating PDF files containing images, the images should not be downsampled. Downsampling does
not preserve all of the pixels in the original. For PDF images, one of the following lossless compression
techniques should be used:
• For lossless compression of color and grayscale images, use Zip/Flate (one technique with two names).
This is specified in Internet RFC 1950 and RFC 1951 (http://www.ietf.org/rfc/rfc1950.txt).
• For lossless compression of black and white images, use the CCITT Group 4 Fax compression
technique. It is specified as CCITT recommendations T.6 (1988) - Facsimile coding schemes and
coding control functions for Group 4 facsimile apparatus.
Paper documents containing hand-written notes should be scanned at a resolution of at least 300 dpi.
Hand-written notes should be done in black ink for clarity. Higher resolution is specifically requested when
scanning documents containing non-Western characters (e.g. Kanji); 600 dpi is recommended.
For photographs, the image should be obtained with a resolution of 600 dpi. If black and white photos are
submitted, 8-bit grayscale images should be considered. If color photos are submitted, 24-bit RGB images
should be considered. A captured image should not be subjected to non-uniform scaling (i.e., sizing).
Gels and karyotypes should be scanned directly, rather than from photographs. Scanning should be at 600
dpi and 8-bit grayscale depth.
Plotter output graphics should be scanned or captured digitally at 300 dpi.
High-pressure liquid chromatography or similar images should be scanned at 300 dpi.

Applicants should validate the quality of the renditions.
Hypertext Linking and Bookmarks

Hypertext links and bookmarks improve navigation through PDF documents. Hypertext links can be
designated by rectangles using thin lines or by blue text as appropriate.
In general, for documents with a table of contents, bookmarks for each item listed in the table of contents
should be provided including all tables, figures, publications, other references, and appendices. Bookmarks
should follow hierarchical level and order of table of contents. These bookmarks are essential for the
efficient navigation through documents. The bookmark hierarchy should be identical to the table of
contents with no additional bookmark levels beyond those present in the table of contents. Each additional
Page 7-3
level increases the need for space to read the bookmarks. The use of no more than 4 levels in the hierarchy
is recommended.
Hypertext links throughout the document to support annotations, related sections, references, appendices,
tables, or figures that are not located on the same page are helpful and improve navigation efficiency.
Relative paths should be used when creating hypertext links to minimize the loss of hyperlink functionality
when folders are moved between disk drives. Absolute links that reference specific drives and root
directories will no longer work once the submission is loaded onto the Agency’s network servers.
When creating bookmarks and hyperlinks, the magnification setting Inherit Zoom should be used so that
the destination page displays at the same magnification level that the reviewer is using for the rest of the
document.
Insufficient experience is available across agencies to provide any formal guidance on whether bookmarks
should be presented expanded or collapsed. It might not be considered appropriate to have all the
bookmarks open since, in some instances, these can be so numerous that they are not useful to the review
and can affect ‘refresh’ time in a web-browser. Equally, it is probably not useful to have the bookmarks
fully closed, since the reviewer would always have to open them. It is recommended, therefore, that the
applicant consider the usefulness to the reviewers of how to present bookmarks and have some level of
consistency across similar document types within the submission.
Page Numbering
Only the internal page numbers of the document are expected (1-n). No additional page/volume numbers
running across documents are expected. It is easier to navigate through an electronic document if the page
numbers for the document and the PDF file are the same. To accomplish this, the first page of the
document should be numbered page 1, and all subsequent pages (including appendices and attachments)
should be numbered consecutively with Arabic numerals. Roman numerals should not be used to number
pages (e.g., title pages, tables of contents) and pages should not be left unnumbered (e.g., title page.)
Numbering in this manner keeps the Acrobat numbering in synchrony with the internal document page
numbers.
The only exception should be where a document is split because of its size (e.g., >100 MB); the second or
subsequent file should be numbered consecutively to that of the first or preceding file.
Document Information Fields

Recommendations for the document information fields will be provided in the regional guidance for the
specific submission type.
Open Dialog Box

The open dialog box sets the document view when the file is opened. The initial view of the PDF files
should be set as Bookmarks and Page. If there are no bookmarks, the initial view as Page only should be
set. The Magnification and Page Layout should be set as default.
Security
No security settings or password protection for PDF files should be included. Security fields should be set
to allow printing, changes to the document, selecting text and graphics, and adding or changing notes and
form fields.
Indexing PDF Documents

There are no current plans in the ICH regions to use full text indexes.
Page 7-4
Use of Acrobat Plug-Ins
It is appropriate to use plug-ins to assist in the creation of a submission. However, the review of the
submission should not call for the use of any plug-ins in addition to those provided with Adobe Acrobat
because agencies will not necessarily have access to the additional plug-in functionality.
XML Files
A working group at the World Wide Web Consortium (W3C) developed XML. It is a nonproprietary
language developed to improve on previous markup languages including standard generalized markup
language (SGML) and hypertext markup language (HTML).
Information in an XML file is divided into specific pieces. These pieces are called objects or element types.
The element type identifies the piece of information. For example, the name of the company submitting a
registration application in eCTD format for review is identified with the element type <applicant>. All
element type names are bracketed using the special characters <>. Inside the XML document, the element
type name is placed just prior to the piece of information and after the information. This is called tagging.
So, in the XML file, the applicant could be tagged as follows: <applicant>Worldwide Pharmaceuticals
Inc.</applicant>. The “/” prior to the element type denotes that this is the end of the information about the
applicant.
It is recognized that there is a general trend towards describing the contents of documents with XML.
However, the current specification supports only the use of XML for structured information. It can be
interpreted from this that the submission of summaries, reports and other narrative documents in XML
format is not currently supported by the specification. Regulatory authorities and applicants could agree to
use other formats regionally (including uses of the common formats in a different way from the above).
Thus, if an applicant wishes to use XML for narrative documents, the applicant should contact the
applicant's own regional regulatory authority, understanding that other regulatory authorities may not
accept these XML files.
By using a hierarchical structure, XML allows you to relate two or more elements. This is accomplished by
nesting one element within another.
Additional information about the element type is provided by attributes. Attributes are placed within the
element types and are surrounded by quotation marks (“ “.) For example, if you wanted to show that the
applicant name is presented in the English language, you could add this piece of information as an attribute.
This could be represented in the XML file as <applicant XML:LANG=“EN”> Worldwide Pharmaceuticals
Inc.</applicant>.
XML files are read by a parser found in Internet browsers. Stylesheets provide the browser with the
information to create tables, fonts, and colors for display.
The specific names of the element types and attributes as well as the valid syntax, structure and format for
defining the XML elements are included in a file called document type definition (DTD). If the XML
document does not follow the DTD, then the file will not be able to be used properly.
The top three lines of the XML file should include the XML version, the stylesheet type and address, and
the DTD name and address.
Additional information about the XML standard can be found at the W3C Web site at www.w3.org.
SVG Files
SVG is a language for describing two-dimensional graphics in XML. SVG allows for three types of
graphic objects: vector graphic shapes (e.g., paths consisting of straight lines and curves), images, and
text. Graphical objects can be grouped, styled, transformed and composited into previously rendered
objects. Text can be in any XML namespace suitable to the application, which enhances searchability
Page 7-5
and accessibility of the SVG graphics. The feature set includes nested transformations, clipping paths,
alpha masks, filter effects, template objects, and extensibility.
SVG drawings can be dynamic and interactive. The Document Object Model (DOM) for SVG, which
includes the full XML DOM, allows for straightforward and efficient vector graphics animation via
scripting. A rich set of event handlers such as onmouseover and onclick can be assigned to any SVG
graphical object. Because of its compatibility and leveraging of other Web standards, features like
scripting can be done on SVG elements and other XML elements from different namespaces
simultaneously within the same Web page. 8
The specific use of SVG in a submission should be discussed with the regulatory authority.
8
This description of SVG is from w3c Web page http://www.w3.org/graphics/svg
Page 7-6
Appendix 8: XML eCTD DTD

<!ENTITY % att " ID ID #IMPLIED


Page 8-1

<!ELEMENT ectd:ectd (m1-administrative-information-and-prescribing-information?, m2-common-technical-
document-summaries?, m3-quality?, m4-nonclinical-study-reports?, m5-clinical-study-reports?)>
<!ATTLIST ectd:ectd
xmlns:ectd CDATA #FIXED "http://www.ich.org/ectd"
dtd-version CDATA #FIXED "3.2"
>



<!ATTLIST leaf
ID ID #REQUIRED
application-version CDATA #IMPLIED
version CDATA #IMPLIED
font-library CDATA #IMPLIED
operation (new | append | replace | delete) #REQUIRED
modified-file CDATA #IMPLIED
checksum CDATA #REQUIRED
checksum-type CDATA #REQUIRED
keywords CDATA #IMPLIED
xlink:href CDATA #IMPLIED
xlink:show (new | replace | embed | other | none) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none) #IMPLIED
>
<!ELEMENT title (#PCDATA)>
<!ATTLIST title
ID ID #IMPLIED
>
<!ELEMENT link-text (#PCDATA | xref)*>
<!ATTLIST link-text
ID ID #IMPLIED
>
<!ATTLIST xref
ID ID #REQUIRED
xlink:title CDATA #REQUIRED
xlink:href CDATA #REQUIRED
xlink:show (new | replace | embed | other | none) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none) #IMPLIED
>
ID ID #IMPLIED
>



<!ELEMENT m1-administrative-information-and-prescribing-information (leaf*)>
<!ATTLIST m1-administrative-information-and-prescribing-information
%att;
>
Page 8-2
<!ELEMENT m2-common-technical-document-summaries (leaf*, m2-2-introduction?, m2-3-quality-overall-
summary?, m2-4-nonclinical-overview?, m2-5-clinical-overview?, m2-6-nonclinical-written-and-tabulated-
summaries?, m2-7-clinical-summary?)>
<!ATTLIST m2-common-technical-document-summaries
%att;
>
<!ELEMENT m2-2-introduction ((leaf | node-extension)*)>
<!ATTLIST m2-2-introduction
%att;
>
<!ELEMENT m2-3-quality-overall-summary (leaf*, m2-3-introduction?, m2-3-s-drug-substance*, m2-3-p-drug-
product*, m2-3-a-appendices?, m2-3-r-regional-information?)>
<!ATTLIST m2-3-quality-overall-summary
%att;
>
<!ELEMENT m2-3-introduction ((leaf | node-extension)*)>
<!ATTLIST m2-3-introduction
%att;
>
<!ELEMENT m2-3-s-drug-substance ((leaf | node-extension)*)>
<!ATTLIST m2-3-s-drug-substance
%att;
substance CDATA #REQUIRED
manufacturer CDATA #REQUIRED
>
<!ELEMENT m2-3-p-drug-product ((leaf | node-extension)*)>
<!ATTLIST m2-3-p-drug-product
%att;
product-name CDATA #IMPLIED
dosageform CDATA #IMPLIED
manufacturer CDATA #IMPLIED
>
<!ELEMENT m2-3-a-appendices ((leaf | node-extension)*)>
<!ATTLIST m2-3-a-appendices
%att;
>
<!ELEMENT m2-3-r-regional-information ((leaf | node-extension)*)>
<!ATTLIST m2-3-r-regional-information
%att;
>
<!ELEMENT m2-4-nonclinical-overview ((leaf | node-extension)*)>
<!ATTLIST m2-4-nonclinical-overview
%att;
>
<!ELEMENT m2-5-clinical-overview ((leaf | node-extension)*)>
<!ATTLIST m2-5-clinical-overview
%att;
>
<!ELEMENT m2-6-nonclinical-written-and-tabulated-summaries (leaf*, m2-6-1-introduction?, m2-6-2-pharmacology-
written-summary?, m2-6-3-pharmacology-tabulated-summary?, m2-6-4-pharmacokinetics-written-summary?, m2-6-5-
pharmacokinetics-tabulated-summary?, m2-6-6-toxicology-written-summary?, m2-6-7-toxicology-tabulated-
summary?)>
<!ATTLIST m2-6-nonclinical-written-and-tabulated-summaries
%att;
>
<!ELEMENT m2-6-1-introduction ((leaf | node-extension)*)>
<!ATTLIST m2-6-1-introduction
%att;
>
<!ELEMENT m2-6-2-pharmacology-written-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-2-pharmacology-written-summary
%att;
Page 8-3
>
<!ELEMENT m2-6-3-pharmacology-tabulated-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-3-pharmacology-tabulated-summary
%att;
>
<!ELEMENT m2-6-4-pharmacokinetics-written-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-4-pharmacokinetics-written-summary
%att;
>
<!ELEMENT m2-6-5-pharmacokinetics-tabulated-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-5-pharmacokinetics-tabulated-summary
%att;
>
<!ELEMENT m2-6-6-toxicology-written-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-6-toxicology-written-summary
%att;
>
<!ELEMENT m2-6-7-toxicology-tabulated-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-7-toxicology-tabulated-summary
%att;
>
<!ELEMENT m2-7-clinical-summary (leaf*, m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analytical-
methods?, m2-7-2-summary-of-clinical-pharmacology-studies?, m2-7-3-summary-of-clinical-efficacy*, m2-7-4-
summary-of-clinical-safety?, m2-7-5-literature-references?, m2-7-6-synopses-of-individual-studies?)>
<!ATTLIST m2-7-clinical-summary
%att;
>
<!ELEMENT m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analytical-methods ((leaf | node-
extension)*)>
<!ATTLIST m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analytical-methods
%att;
>
<!ELEMENT m2-7-2-summary-of-clinical-pharmacology-studies ((leaf | node-extension)*)>
<!ATTLIST m2-7-2-summary-of-clinical-pharmacology-studies
%att;
>
<!ELEMENT m2-7-3-summary-of-clinical-efficacy ((leaf | node-extension)*)>
<!ATTLIST m2-7-3-summary-of-clinical-efficacy
%att;
>
<!ELEMENT m2-7-4-summary-of-clinical-safety ((leaf | node-extension)*)>
<!ATTLIST m2-7-4-summary-of-clinical-safety
%att;
>
<!ELEMENT m2-7-5-literature-references ((leaf | node-extension)*)>
<!ATTLIST m2-7-5-literature-references
%att;
>
<!ELEMENT m2-7-6-synopses-of-individual-studies ((leaf | node-extension)*)>
<!ATTLIST m2-7-6-synopses-of-individual-studies
%att;
>
<!ELEMENT m3-quality (leaf*, m3-2-body-of-data?, m3-3-literature-references?)>
<!ATTLIST m3-quality
%att;
>
<!ELEMENT m3-2-body-of-data (leaf*, m3-2-s-drug-substance*, m3-2-p-drug-product*, m3-2-a-appendices?, m3-2-r-
regional-information?)>
<!ATTLIST m3-2-body-of-data
%att;
>
Page 8-4
<!ELEMENT m3-2-s-drug-substance (leaf*, m3-2-s-1-general-information?, m3-2-s-2-manufacture?, m3-2-s-3-
characterisation?, m3-2-s-4-control-of-drug-substance?, m3-2-s-5-reference-standards-or-materials?, m3-2-s-6-
container-closure-system?, m3-2-s-7-stability?)>
<!ATTLIST m3-2-s-drug-substance
%att;
substance CDATA #REQUIRED
manufacturer CDATA #REQUIRED
>
<!ELEMENT m3-2-s-1-general-information (leaf*, m3-2-s-1-1-nomenclature?, m3-2-s-1-2-structure?, m3-2-s-1-3-
general-properties?)>
<!ATTLIST m3-2-s-1-general-information
%att;
>
<!ELEMENT m3-2-s-1-1-nomenclature ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-1-1-nomenclature
%att;
>
<!ELEMENT m3-2-s-1-2-structure ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-1-2-structure
%att;
>
<!ELEMENT m3-2-s-1-3-general-properties ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-1-3-general-properties
%att;
>
<!ELEMENT m3-2-s-2-manufacture (leaf*, m3-2-s-2-1-manufacturer?, m3-2-s-2-2-description-of-manufacturing-
process-and-process-controls?, m3-2-s-2-3-control-of-materials?, m3-2-s-2-4-controls-of-critical-steps-and-
intermediates?, m3-2-s-2-5-process-validation-and-or-evaluation?, m3-2-s-2-6-manufacturing-process-development?)>
<!ATTLIST m3-2-s-2-manufacture
%att;
>
<!ELEMENT m3-2-s-2-1-manufacturer ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-1-manufacturer
%att;
>
<!ELEMENT m3-2-s-2-2-description-of-manufacturing-process-and-process-controls ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-2-description-of-manufacturing-process-and-process-controls
%att;
>
<!ELEMENT m3-2-s-2-3-control-of-materials ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-3-control-of-materials
%att;
>
<!ELEMENT m3-2-s-2-4-controls-of-critical-steps-and-intermediates ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-4-controls-of-critical-steps-and-intermediates
%att;
>
<!ELEMENT m3-2-s-2-5-process-validation-and-or-evaluation ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-5-process-validation-and-or-evaluation
%att;
>
<!ELEMENT m3-2-s-2-6-manufacturing-process-development ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-6-manufacturing-process-development
%att;
>
<!ELEMENT m3-2-s-3-characterisation (leaf*, m3-2-s-3-1-elucidation-of-structure-and-other-characteristics?, m3-2-s-
3-2-impurities?)>
<!ATTLIST m3-2-s-3-characterisation
%att;
>
<!ELEMENT m3-2-s-3-1-elucidation-of-structure-and-other-characteristics ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-3-1-elucidation-of-structure-and-other-characteristics
Page 8-5
%att;
>
<!ELEMENT m3-2-s-3-2-impurities ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-3-2-impurities
%att;
>
<!ELEMENT m3-2-s-4-control-of-drug-substance (leaf*, m3-2-s-4-1-specification?, m3-2-s-4-2-analytical-
procedures?, m3-2-s-4-3-validation-of-analytical-procedures?, m3-2-s-4-4-batch-analyses?, m3-2-s-4-5-justification-of-
specification?)>
<!ATTLIST m3-2-s-4-control-of-drug-substance
%att;
>
<!ELEMENT m3-2-s-4-1-specification ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-1-specification
%att;
>
<!ELEMENT m3-2-s-4-2-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-2-analytical-procedures
%att;
>
<!ELEMENT m3-2-s-4-3-validation-of-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-3-validation-of-analytical-procedures
%att;
>
<!ELEMENT m3-2-s-4-4-batch-analyses ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-4-batch-analyses
%att;
>
<!ELEMENT m3-2-s-4-5-justification-of-specification ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-5-justification-of-specification
%att;
>
<!ELEMENT m3-2-s-5-reference-standards-or-materials ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-5-reference-standards-or-materials
%att;
>
<!ELEMENT m3-2-s-6-container-closure-system ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-6-container-closure-system
%att;
>
<!ELEMENT m3-2-s-7-stability (leaf*, m3-2-s-7-1-stability-summary-and-conclusions?, m3-2-s-7-2-post-approval-
stability-protocol-and-stability-commitment?, m3-2-s-7-3-stability-data?)>
<!ATTLIST m3-2-s-7-stability
%att;
>
<!ELEMENT m3-2-s-7-1-stability-summary-and-conclusions ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-7-1-stability-summary-and-conclusions
%att;
>
<!ELEMENT m3-2-s-7-2-post-approval-stability-protocol-and-stability-commitment ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-7-2-post-approval-stability-protocol-and-stability-commitment
%att;
>
<!ELEMENT m3-2-s-7-3-stability-data ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-7-3-stability-data
%att;
>
<!ELEMENT m3-2-p-drug-product (leaf*, m3-2-p-1-description-and-composition-of-the-drug-product?, m3-2-p-2-
pharmaceutical-development?, m3-2-p-3-manufacture?, m3-2-p-4-control-of-excipients*, m3-2-p-5-control-of-drug-
product?, m3-2-p-6-reference-standards-or-materials?, m3-2-p-7-container-closure-system?, m3-2-p-8-stability?)>
<!ATTLIST m3-2-p-drug-product
%att;
Page 8-6
>
<!ELEMENT m3-2-p-1-description-and-composition-of-the-drug-product ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-1-description-and-composition-of-the-drug-product
%att;
>
<!ELEMENT m3-2-p-2-pharmaceutical-development ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-2-pharmaceutical-development
%att;
>
<!ELEMENT m3-2-p-3-manufacture (leaf*, m3-2-p-3-1-manufacturers?, m3-2-p-3-2-batch-formula?, m3-2-p-3-3-
description-of-manufacturing-process-and-process-controls?, m3-2-p-3-4-controls-of-critical-steps-and-intermediates?,
m3-2-p-3-5-process-validation-and-or-evaluation?)>
<!ATTLIST m3-2-p-3-manufacture
%att;
>
<!ELEMENT m3-2-p-3-1-manufacturers ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-3-1-manufacturers
%att;
>
<!ELEMENT m3-2-p-3-2-batch-formula ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-3-2-batch-formula
%att;
>
<!ELEMENT m3-2-p-3-3-description-of-manufacturing-process-and-process-controls ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-3-3-description-of-manufacturing-process-and-process-controls
%att;
>
<!ELEMENT m3-2-p-3-4-controls-of-critical-steps-and-intermediates ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-3-4-controls-of-critical-steps-and-intermediates
%att;
>
<!ELEMENT m3-2-p-3-5-process-validation-and-or-evaluation ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-3-5-process-validation-and-or-evaluation
%att;
>
<!ELEMENT m3-2-p-4-control-of-excipients (leaf*, m3-2-p-4-1-specifications?, m3-2-p-4-2-analytical-procedures?,
m3-2-p-4-3-validation-of-analytical-procedures?, m3-2-p-4-4-justification-of-specifications?, m3-2-p-4-5-excipients-
of-human-or-animal-origin?, m3-2-p-4-6-novel-excipients?)>
<!ATTLIST m3-2-p-4-control-of-excipients
%att;
excipient CDATA #IMPLIED
>
<!ELEMENT m3-2-p-4-1-specifications ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-1-specifications
%att;
>
<!ELEMENT m3-2-p-4-2-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-2-analytical-procedures
%att;
>
<!ELEMENT m3-2-p-4-3-validation-of-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-3-validation-of-analytical-procedures
%att;
>
<!ELEMENT m3-2-p-4-4-justification-of-specifications ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-4-justification-of-specifications
%att;
>
<!ELEMENT m3-2-p-4-5-excipients-of-human-or-animal-origin ((leaf | node-extension)*)>
Page 8-7
<!ATTLIST m3-2-p-4-5-excipients-of-human-or-animal-origin
%att;
>
<!ELEMENT m3-2-p-4-6-novel-excipients ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-6-novel-excipients
%att;
>
<!ELEMENT m3-2-p-5-control-of-drug-product (leaf*, m3-2-p-5-1-specifications?, m3-2-p-5-2-analytical-
procedures?, m3-2-p-5-3-validation-of-analytical-procedures?, m3-2-p-5-4-batch-analyses?, m3-2-p-5-5-
characterisation-of-impurities?, m3-2-p-5-6-justification-of-specifications?)>
<!ATTLIST m3-2-p-5-control-of-drug-product
%att;
>
<!ELEMENT m3-2-p-5-1-specifications ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-1-specifications
%att;
>
<!ELEMENT m3-2-p-5-2-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-2-analytical-procedures
%att;
>
<!ELEMENT m3-2-p-5-3-validation-of-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-3-validation-of-analytical-procedures
%att;
>
<!ELEMENT m3-2-p-5-4-batch-analyses ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-4-batch-analyses
%att;
>
<!ELEMENT m3-2-p-5-5-characterisation-of-impurities ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-5-characterisation-of-impurities
%att;
>
<!ELEMENT m3-2-p-5-6-justification-of-specifications ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-6-justification-of-specifications
%att;
>
<!ELEMENT m3-2-p-6-reference-standards-or-materials ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-6-reference-standards-or-materials
%att;
>
<!ELEMENT m3-2-p-7-container-closure-system ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-7-container-closure-system
%att;
>
<!ELEMENT m3-2-p-8-stability (leaf*, m3-2-p-8-1-stability-summary-and-conclusion?, m3-2-p-8-2-post-approval-
stability-protocol-and-stability-commitment?, m3-2-p-8-3-stability-data?)>
<!ATTLIST m3-2-p-8-stability
%att;
>
<!ELEMENT m3-2-p-8-1-stability-summary-and-conclusion ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-8-1-stability-summary-and-conclusion
%att;
>
<!ELEMENT m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment
%att;
>
<!ELEMENT m3-2-p-8-3-stability-data ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-8-3-stability-data
%att;
>
Page 8-8
<!ELEMENT m3-2-a-appendices (leaf*, m3-2-a-1-facilities-and-equipment*, m3-2-a-2-adventitious-agents-safety-
evaluation*, m3-2-a-3-excipients?)>
<!ATTLIST m3-2-a-appendices
%att;
>
<!ELEMENT m3-2-a-1-facilities-and-equipment ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-1-facilities-and-equipment
%att;
substance CDATA #IMPLIED
>
<!ELEMENT m3-2-a-2-adventitious-agents-safety-evaluation ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-2-adventitious-agents-safety-evaluation
%att;
substance CDATA #IMPLIED
>
<!ELEMENT m3-2-a-3-excipients ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-3-excipients
%att;
>
<!ELEMENT m3-2-r-regional-information ((leaf | node-extension)*)>
<!ATTLIST m3-2-r-regional-information
%att;
>
<!ELEMENT m3-3-literature-references ((leaf | node-extension)*)>
<!ATTLIST m3-3-literature-references
%att;
>
<!ELEMENT m4-nonclinical-study-reports (leaf*, m4-2-study-reports?, m4-3-literature-references?)>
<!ATTLIST m4-nonclinical-study-reports
%att;
>
<!ELEMENT m4-2-study-reports (leaf*, m4-2-1-pharmacology?, m4-2-2-pharmacokinetics?, m4-2-3-toxicology?)>
<!ATTLIST m4-2-study-reports
%att;
>
<!ELEMENT m4-2-1-pharmacology (leaf*, m4-2-1-1-primary-pharmacodynamics?, m4-2-1-2-secondary-
pharmacodynamics?, m4-2-1-3-safety-pharmacology?, m4-2-1-4-pharmacodynamic-drug-interactions?)>
<!ATTLIST m4-2-1-pharmacology
%att;
>
<!ELEMENT m4-2-1-1-primary-pharmacodynamics ((leaf | node-extension)*)>
<!ATTLIST m4-2-1-1-primary-pharmacodynamics
%att;
>
<!ELEMENT m4-2-1-2-secondary-pharmacodynamics ((leaf | node-extension)*)>
<!ATTLIST m4-2-1-2-secondary-pharmacodynamics
%att;
>
<!ELEMENT m4-2-1-3-safety-pharmacology ((leaf | node-extension)*)>
<!ATTLIST m4-2-1-3-safety-pharmacology
%att;
>
<!ELEMENT m4-2-1-4-pharmacodynamic-drug-interactions ((leaf | node-extension)*)>
<!ATTLIST m4-2-1-4-pharmacodynamic-drug-interactions
%att;
>
Page 8-9
<!ELEMENT m4-2-2-pharmacokinetics (leaf*, m4-2-2-1-analytical-methods-and-validation-reports?, m4-2-2-2-
absorption?, m4-2-2-3-distribution?, m4-2-2-4-metabolism?, m4-2-2-5-excretion?, m4-2-2-6-pharmacokinetic-drug-
interactions?, m4-2-2-7-other-pharmacokinetic-studies?)>
<!ATTLIST m4-2-2-pharmacokinetics
%att;
>
<!ELEMENT m4-2-2-1-analytical-methods-and-validation-reports ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-1-analytical-methods-and-validation-reports
%att;
>
<!ELEMENT m4-2-2-2-absorption ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-2-absorption
%att;
>
<!ELEMENT m4-2-2-3-distribution ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-3-distribution
%att;
>
<!ELEMENT m4-2-2-4-metabolism ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-4-metabolism
%att;
>
<!ELEMENT m4-2-2-5-excretion ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-5-excretion
%att;
>
<!ELEMENT m4-2-2-6-pharmacokinetic-drug-interactions ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-6-pharmacokinetic-drug-interactions
%att;
>
<!ELEMENT m4-2-2-7-other-pharmacokinetic-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-7-other-pharmacokinetic-studies
%att;
>
<!ELEMENT m4-2-3-toxicology (leaf*, m4-2-3-1-single-dose-toxicity?, m4-2-3-2-repeat-dose-toxicity?, m4-2-3-3-
genotoxicity?, m4-2-3-4-carcinogenicity?, m4-2-3-5-reproductive-and-developmental-toxicity?, m4-2-3-6-local-
tolerance?, m4-2-3-7-other-toxicity-studies?)>
<!ATTLIST m4-2-3-toxicology
%att;
>
<!ELEMENT m4-2-3-1-single-dose-toxicity ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-1-single-dose-toxicity
%att;
>
<!ELEMENT m4-2-3-2-repeat-dose-toxicity ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-2-repeat-dose-toxicity
%att;
>
<!ELEMENT m4-2-3-3-genotoxicity (leaf*, m4-2-3-3-1-in-vitro?, m4-2-3-3-2-in-vivo?)>
<!ATTLIST m4-2-3-3-genotoxicity
%att;
>
<!ELEMENT m4-2-3-3-1-in-vitro ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-3-1-in-vitro
%att;
>
<!ELEMENT m4-2-3-3-2-in-vivo ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-3-2-in-vivo
%att;
>
<!ELEMENT m4-2-3-4-carcinogenicity (leaf*, m4-2-3-4-1-long-term-studies?, m4-2-3-4-2-short-or-medium-term-
studies?, m4-2-3-4-3-other-studies?)>
Page 8-10
<!ATTLIST m4-2-3-4-carcinogenicity
%att;
>
<!ELEMENT m4-2-3-4-1-long-term-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-4-1-long-term-studies
%att;
>
<!ELEMENT m4-2-3-4-2-short-or-medium-term-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-4-2-short-or-medium-term-studies
%att;
>
<!ELEMENT m4-2-3-4-3-other-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-4-3-other-studies
%att;
>
<!ELEMENT m4-2-3-5-reproductive-and-developmental-toxicity (leaf*, m4-2-3-5-1-fertility-and-early-embryonic-
development?, m4-2-3-5-2-embryo-fetal-development?, m4-2-3-5-3-prenatal-and-postnatal-development-including-
maternal-function?, m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated?)>
<!ATTLIST m4-2-3-5-reproductive-and-developmental-toxicity
%att;
>
<!ELEMENT m4-2-3-5-1-fertility-and-early-embryonic-development ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-1-fertility-and-early-embryonic-development
%att;
>
<!ELEMENT m4-2-3-5-2-embryo-fetal-development ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-2-embryo-fetal-development
%att;
>
<!ELEMENT m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
%att;
>
<!ELEMENT m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated ((leaf |
node-extension)*)>
<!ATTLIST m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
%att;
>
<!ELEMENT m4-2-3-6-local-tolerance ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-6-local-tolerance
%att;
>
<!ELEMENT m4-2-3-7-other-toxicity-studies (leaf*, m4-2-3-7-1-antigenicity?, m4-2-3-7-2-immunotoxicity?, m4-2-3-
7-3-mechanistic-studies?, m4-2-3-7-4-dependence?, m4-2-3-7-5-metabolites?, m4-2-3-7-6-impurities?, m4-2-3-7-7-
other?)>
<!ATTLIST m4-2-3-7-other-toxicity-studies
%att;
>
<!ELEMENT m4-2-3-7-1-antigenicity ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-1-antigenicity
%att;
>
<!ELEMENT m4-2-3-7-2-immunotoxicity ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-2-immunotoxicity
%att;
>
<!ELEMENT m4-2-3-7-3-mechanistic-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-3-mechanistic-studies
%att;
>
<!ELEMENT m4-2-3-7-4-dependence ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-4-dependence
Page 8-11
%att;
>
<!ELEMENT m4-2-3-7-5-metabolites ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-5-metabolites
%att;
>
<!ELEMENT m4-2-3-7-6-impurities ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-6-impurities
%att;
>
<!ELEMENT m4-2-3-7-7-other ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-7-other
%att;
>
%att;
>
<!ELEMENT m5-clinical-study-reports (leaf*, m5-2-tabular-listing-of-all-clinical-studies?, m5-3-clinical-study-
reports?, m5-4-literature-references?)>
<!ATTLIST m5-clinical-study-reports
%att;
>
<!ELEMENT m5-2-tabular-listing-of-all-clinical-studies ((leaf | node-extension)*)>
<!ATTLIST m5-2-tabular-listing-of-all-clinical-studies
%att;
>
<!ELEMENT m5-3-clinical-study-reports (leaf*, m5-3-1-reports-of-biopharmaceutic-studies?, m5-3-2-reports-of-
studies-pertinent-to-pharmacokinetics-using-human-biomaterials?, m5-3-3-reports-of-human-pharmacokinetics-pk-
studies?, m5-3-4-reports-of-human-pharmacodynamics-pd-studies?, m5-3-5-reports-of-efficacy-and-safety-studies*,
m5-3-6-reports-of-postmarketing-experience?, m5-3-7-case-report-forms-and-individual-patient-listings?)>
<!ATTLIST m5-3-clinical-study-reports
%att;
>
<!ELEMENT m5-3-1-reports-of-biopharmaceutic-studies (leaf*, m5-3-1-1-bioavailability-study-reports?, m5-3-1-2-
comparative-ba-and-bioequivalence-study-reports?, m5-3-1-3-in-vitro-in-vivo-correlation-study-reports?, m5-3-1-4-
reports-of-bioanalytical-and-analytical-methods-for-human-studies?)>
<!ATTLIST m5-3-1-reports-of-biopharmaceutic-studies
%att;
>
<!ELEMENT m5-3-1-1-bioavailability-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-1-1-bioavailability-study-reports
%att;
>
<!ELEMENT m5-3-1-2-comparative-ba-and-bioequivalence-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
%att;
>
<!ELEMENT m5-3-1-3-in-vitro-in-vivo-correlation-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
%att;
>
<!ELEMENT m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies ((leaf | node-extension)*)>
<!ATTLIST m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
%att;
>
<!ELEMENT m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials (leaf*, m5-3-2-1-
plasma-protein-binding-study-reports?, m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies?, m5-3-
2-3-reports-of-studies-using-other-human-biomaterials?)>
<!ATTLIST m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials
%att;
>
Page 8-12
<!ELEMENT m5-3-2-1-plasma-protein-binding-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-2-1-plasma-protein-binding-study-reports
%att;
>
<!ELEMENT m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies ((leaf | node-extension)*)>
<!ATTLIST m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
%att;
>
<!ELEMENT m5-3-2-3-reports-of-studies-using-other-human-biomaterials ((leaf | node-extension)*)>
<!ATTLIST m5-3-2-3-reports-of-studies-using-other-human-biomaterials
%att;
>
<!ELEMENT m5-3-3-reports-of-human-pharmacokinetics-pk-studies (leaf*, m5-3-3-1-healthy-subject-pk-and-initial-
tolerability-study-reports?, m5-3-3-2-patient-pk-and-initial-tolerability-study-reports?, m5-3-3-3-intrinsic-factor-pk-
study-reports?, m5-3-3-4-extrinsic-factor-pk-study-reports?, m5-3-3-5-population-pk-study-reports?)>
<!ATTLIST m5-3-3-reports-of-human-pharmacokinetics-pk-studies
%att;
>
<!ELEMENT m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
%att;
>
<!ELEMENT m5-3-3-2-patient-pk-and-initial-tolerability-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
%att;
>
<!ELEMENT m5-3-3-3-intrinsic-factor-pk-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-3-intrinsic-factor-pk-study-reports
%att;
>
<!ELEMENT m5-3-3-4-extrinsic-factor-pk-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-4-extrinsic-factor-pk-study-reports
%att;
>
<!ELEMENT m5-3-3-5-population-pk-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-5-population-pk-study-reports
%att;
>
<!ELEMENT m5-3-4-reports-of-human-pharmacodynamics-pd-studies (leaf*, m5-3-4-1-healthy-subject-pd-and-pk-
pd-study-reports?, m5-3-4-2-patient-pd-and-pk-pd-study-reports?)>
<!ATTLIST m5-3-4-reports-of-human-pharmacodynamics-pd-studies
%att;
>
<!ELEMENT m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
%att;
>
<!ELEMENT m5-3-4-2-patient-pd-and-pk-pd-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-4-2-patient-pd-and-pk-pd-study-reports
%att;
>
<!ELEMENT m5-3-5-reports-of-efficacy-and-safety-studies (leaf*, m5-3-5-1-study-reports-of-controlled-clinical-
studies-pertinent-to-the-claimed-indication?, m5-3-5-2-study-reports-of-uncontrolled-clinical-studies?, m5-3-5-3-
reports-of-analyses-of-data-from-more-than-one-study?, m5-3-5-4-other-study-reports?)>
<!ATTLIST m5-3-5-reports-of-efficacy-and-safety-studies
%att;
>
<!ELEMENT m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication ((leaf | node-
extension)*)>
<!ATTLIST m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
%att;
Page 8-13
>
<!ELEMENT m5-3-5-2-study-reports-of-uncontrolled-clinical-studies ((leaf | node-extension)*)>
<!ATTLIST m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
%att;
>
<!ELEMENT m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study ((leaf | node-extension)*)>
<!ATTLIST m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
%att;
>
<!ELEMENT m5-3-5-4-other-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-5-4-other-study-reports
%att;
>
<!ELEMENT m5-3-6-reports-of-postmarketing-experience ((leaf | node-extension)*)>
<!ATTLIST m5-3-6-reports-of-postmarketing-experience
%att;
>
<!ELEMENT m5-3-7-case-report-forms-and-individual-patient-listings ((leaf | node-extension)*)>
<!ATTLIST m5-3-7-case-report-forms-and-individual-patient-listings
%att;
>
%att;
>
Page 8-14
ICH eCTD STF Specification V 2.6.1 3-June-2008
INTERNATIONAL CONFERENCE ON HARMONISATION OF

TECHNICAL REQUIREMENTS FOR REGISTRATION OF
PHARMACEUTICALS FOR HUMAN USE
ICH M2 EWG
The eCTD Backbone File Specification for Study Tagging Files
This specification has been developed by the ICH M2 Expert Working

Group and maintained by the eCTD Implementation Working Group in
accordance with the ICH Process as pertains to the M2 EWG and eCTD
change control as it pertains to the eCTD IWG.
The eCTD Backbone Files Specification for Study Tagging Files
Revision History
2004-03-09 1.1 Clarifications to the original version. Constraints from original version
including redundancy of information found in the index.xml file. Added
duration category and values. Added "other" as route of administration
value. Added new name attribute values for file tag element.
Versions between 1.1 and 2.6 have been unpublished drafts
2004-11-17 2.6 Provides specification for both Cumulative and Accumulative
Approaches for presentation of the Study Tagging Files (STF) with
more detailed examples showing index and stf file relationships.
Introduces ich-stf-v2-2.dtd, ich-stf-stylesheet-2-2.xsl and valid-
values.xml.
2008-06-03 2.6.1 Removed Cumulative Approach to STF life cycle management and
made accumulative approach the only option. Provided clarifications
and corrections to text.
Page 2
THE SPECIFICATION FOR STUDY TAGGING FILES (STF) ............................................ 4

I. START AND STOP OF THE STF........................................................................................ 4
II. STUDY-IDENTIFIER ELEMENT ........................................................................................ 5
A. Title Element .................................................................................................................. 5
B. study-id Element............................................................................................................. 5
C. Category Element........................................................................................................... 5
III. STUDY-DOCUMENT AND DOC-CONTENT ELEMENTS .................................................... 7
A. Property element ............................................................................................................ 7
B. File-tag element ............................................................................................................. 7
IV. LIFECYCLE MANAGEMENT OF THE STUDY TAGGING FILE .......................................... 10
V. MODIFYING STF INFORMATION .......................................................................... 11
A. Changes to the STF Study Identifier Information ........................................................ 11
B. Changes to STF Study Document Information............................................................. 13
VI. STUDY DATA MANAGEMENT OPTIONS.............................................................. 16
A. Distinguishing Time-Specific Analyses Within the Same Subsection of the CTD........ 16
B. Presenting Information from One Study in a Different Subsection of the CTD........... 16
VII. EXAMPLE SCENARIO ................................................................................................. 17
Page 3
The Specification for Study Tagging Files (STF)

In order to help identify all of the files associated with a study, information is needed on
each document including the document title, subject matter (defined by the headings
under which the documents are located in the table of contents), relationship to other
documents (e.g., all documents for a specific study report are related to one another),
revision information (i.e., new, replace, delete, append), the location of the document and
information on the sequence that included the document. The eCTD backbone files (e.g.,
index.xml and us-regional.xml) include many of those information items. However, the
eCTD backbone files do not contain enough information on the subject matter of several
documents (e.g., study report documents) to support certain regulatory uses. This
additional information is provided in the STF.
An STF should be provided with the submission of any file, or group of files belonging to
a study in Modules 4 and 5. STFs are required by the United States, are not required in
Europe and are not allowed in Japan. The STF provides for additional heading elements
and heading attributes not currently provided by the eCTD DTD. In the STF, heading
elements are called file-tags and are included in the doc-content element. Heading
attributes are included in the study-identifier element.
Refer to regional guidance for information on STF applicability.
I. START AND STOP OF THE STF
The STF is an XML instance controlled by the ICH STF Document Type Definition
(DTD). The most recent DTD can be found on the ICH web site (www.ich.org). The
DTD should be placed in the dtd subfolder of the util folder. The stylesheet should be in
the style subfolder of the util folder. You should provide a separate STF for each study in
a sequence. The name for the STF XML file should start with the term "stf-" followed by
the alphanumeric code used by the sponsor to unambiguously identify the study (i.e.,
study-id described below) and followed by ".xml" to complete the file name.
For every submission to FDA that includes one or more files pertaining to a specific
study, you should provide an STF. You should place the STF for the specific study in the
module folder with the corresponding study files. You should place a leaf element for the
STF in the appropriate Module 4 or 5 eCTD Table of Contents element in the index.xml
file for that sequence. The operation attribute for this leaf should have a value of "new"
for the first STF for that specific study in that eCTD element and "append" for any
subsequent STF for that same study in that eCTD element (see "Lifecycle Management
of the Study Tagging File"). Subsequent STF files should only include information on the
study documents being provided or modified by the subsequent sequence. The
subsequent STF should always have a modified-file attribute that refers to the most
recently submitted STF provided for that study in that eCTD element (i.e., you should not
continually “append” to the original STF). The version attribute for leaf elements
referencing a STF should cite the version of the STF DTD used to prepare that STF (e.g.,
Page 4
“STF version 2.2”) to allow the development of tools that can either ignore or highlight
the presence of STF XML files.
The STF root element is ectd:study. The STF root element contains two child elements.
The prolog part of the STF XML document and the STF root element contain information
about the following:
1. Version of XML being used
2. Type of characters that are allowed in the file
3. Location of the standards that control the organization of the STF
4. Indication that the file information is ended (end tag)
A sample of the root element and last line of the STF is provided below:

<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-
stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-
version="2.2" xmlns:xlink="http://www.w3.org/1999/xlink">

</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on
the location where the STF instance is stored.
II. STUDY-IDENTIFIER ELEMENT
Information describing the study is contained in the study-identifier element of the STF.
There are three elements contained in the study-identifier element: title, study-id, and
category.
A. Title Element
The title element provides the full title of the study, not the title of each individual
document.
B. study-id Element
The study-id is the internal alphanumeric code used by the sponsor to unambiguously
identify this study.
C. Category Element
The category element provides an additional level of study organization not currently
provided by the eCTD DTD. This element is only relevant for studies provided in the
specific CTD sections cited below.
Page 5
• 4.2.3.1 Single dose toxicity (grouped by species and route of administration)

• 4.2.3.2 Repeat dose toxicity (grouped by species, route of administration, and
duration if applicable)
• 4.2.3.4.1 Long term [carcinogenicity] studies (grouped by species)
• 5.3.5.1 Study reports of controlled clinical studies pertinent to the claimed
indication (grouped by type of control)
Other studies do not call for any category elements. When appropriate, you should place
the category elements at the same level as the title and study-id elements. Each category
element has the attributes name and info-type. Attribute and element values should be
selected from the following table. The info-type attribute value should be "ich" for ICH
approved values or one of the regional values (e.g., "jp", "eu", "ca", "us") for region
specific values.
Category Element values for "category" element

Attributes and Values content choices
name="species"
info-type="ich" mouse
info-type="ich" rat
info-type="ich" hamster
info-type="ich" other-rodent
info-type="ich" rabbit
info-type="ich" dog
info-type="ich" non-human-primate
info-type="ich" other-non-rodent-mammal
info-type="ich" non-mammals
name="route-of-admin"
info-type="ich" oral
info-type="ich" intravenous
info-type="ich" intramuscular
info-type="ich" intraperitoneal
info-type="ich" subcutaneous
info-type="ich" inhalation
info-type="ich" topical
info-type="ich" other ( 1 see footnote)
name="duration"
info-type="us" short
info-type="us" medium
info-type="us" long
name="type-of-control"
info-type="ich" placebo
info-type="ich" no-treatment
info-type="ich" dose-response-without-placebo
1
Please consult the regional authorities before using "other".
Page 6
Category Element values for "category" element

info-type="ich" active-control-without-placebo
info-type="ich" external
The following is an example of the use of the study-identifier elements in an STF for a
long term carcinogenicity study conducted in mice (species="mouse"):
<study-identifier>
<title>Long term carcinogenicity study</title>
<study-id>abc123xyz789</study-id>
<category name="species" info-type="ich" >mouse</category>
<category name="duration" info-type="us" >long</category>
</study-identifier>
III. STUDY-DOCUMENT AND DOC-CONTENT ELEMENTS
The study-document element contains information on the subject matter of each file that
is cited as part of the documentation for a study. The study-document element includes
the doc-content element. The doc-content element contains the property and file-tag
elements.
A. Property element
The property element is appropriate when files might need to be grouped by an applicant
provided value. Currently, this element should only be used for site identification within
a study. For example, in the submission of case-report-forms, multiple forms originating
from the same study site should all be grouped by the study site property element.
Property Element values for "property" element

name="site-identifier" User identified value for the site of the
info-type="us" study.
B. File-tag element
The file-tag element contains the attributes name and info-type. The text value of the file-
tag element's name attribute indicates the subject matter of the document. The value of
the file-tag name attribute should be selected from the values in the table below. For the
value of the info-type attribute, you should use "ich" if using an ICH value or one of the
regional values if the value is not defined in ICH. The table below shows the specified
name attribute values for the file-tag element.
Page 7
name attribute values info- E3

for the file-tag element type Content of Document Reference
(name=" ") value
pre-clinical-study-report ich Pre-clinical study report ( 2 see footnote)
legacy-clinical-study- ich Clinical study report submitted as one
report file (2see footnote)
synopsis ich Study Report Synopsis 2
study-report-body ich Study Report Body 1,3 to 15
protocol-or-amendment ich Protocol and/or amendments 16.1.1
sample-case-report-form ich Sample CRF 16.1.2
iec-irb-consent-form-list ich IEC and IRB and Consent Form 16.1.3
Listings
list-description- ich 16.1.4
investigator-site Description of Investigators and Sites
signatures-investigators ich Signatures of principal or coordinating 16.1.5

investigator(s) or sponsor’s responsible
officer
list-patients-with- ich 16.1.6
Listing of patients receiving test
batches
drug(s) from specified batch
randomisation-scheme ich Randomisation Scheme 16.1.7
audit-certificates-report ich Audit Certificates or similar 16.1.8
documentation
statistical-methods- ich Documentation of statistical methods 16.1.9
interim-analysis-plan and interim analysis plans
inter-laboratory- ich 16.1.10
standardisation- Documentation of Inter-laboratory
methods-quality- Standardization Methods and Quality
assurance Assurance or similar documentation
publications-based-on- ich 16.1.11

study Publications Based on the Study
publications-referenced- ich Publications Referenced in the Study 16.1.12

in-report Report
discontinued-patients ich Discontinued Patients Listing 16.2.1
protocol-deviations ich 16.2.2
Protocol Deviation Listing
2
Refer to M4: Organisation Document, Granularity Annex for instructions on how to typically construct
study reports.
Page 8

(name=" ") value
patients-excluded-from- ich Patients Excluded from Efficacy 16.2.3
efficacy-analysis Analysis Listing
demographic-data ich Demographic Data Listing 16.2.4
compliance-and-drug- ich Compliance and/or Drug Concentration 16.2.5
concentration-data Data Listing
individual-efficacy- ich Individual Efficacy Response Data 16.2.6
response-data Listing
adverse-event-listings ich File contains Adverse Event Listings 16.2.7
listing-individual- ich 16.2.8
laboratory- Individual Laboratory Measurements
measurements-by- Listed by Patient
patient
case-report-forms ich CRF for an individual subject. If you 16.3
are submitting in the US, you should
also provide a "property" element,
described below, with its "name"
attribute = "site-identifier" and its value
the site identification where the study
was performed.
available-on-request ich A file listing documents available upon
request for a single study. Consult
regional guidance for use.
complete-patient-list jp Complete patient list
serious-adverse-event- jp List of patients having serious adverse
patient-list events
adverse-event-patient- jp
List of patients having adverse events
list
abnormal-lab-values- jp List of patients having abnormal lab
patient-list values
data-tabulation-dataset us Data tabulation dataset
data-tabulation-data- us Data definitions for data tabulation
definition datasets
data-listing-dataset us Data listing dataset
data-listing-data- us
Data definitions for data listing datasets
definition
analysis-dataset us Analysis datasets
analysis-program us Program file for analysis dataset
analysis-data-definition us Data definition for analysis datasets
annotated-crf us Annotated CRF for datasets
ecg us Annotated ECG waveform dataset
image us Image files
Page 9

(name=" ") value
subject-profiles us Subject profile. You should also
provide a "property" element, described
below, with its "name" attribute = "site-
identifier" and its value the site
identification where the study was
performed.
safety-report us IND safety report
antibacterial us Antibacterial microbiology report
special-pathogen us Special pathogens (e.g., fungi,
parasites, mycobacteria) and immune
modulator microbiology report
antiviral us Antiviral microbiology report
iss us Integrated analysis of safety –
integrated summary of safety report
ise us Integrated analysis of efficacy –
integrated summary of efficacy report
pm-description us Postmarketing periodic adverse event
drug experience report description
When submitting in the US using a file-tag element with the name attribute value of
"subject-profile" or "case-report-forms", you should include a property element with the
name attribute value "site-identifier" and info-type value "us". The content of the property
element should be text that identifies the site.
IV. LIFECYCLE MANAGEMENT OF THE STUDY TAGGING FILE
When additional leaf elements are to be referenced by a particular STF, the applicant
does not need to submit a complete enumeration of the categories, file-tags and leaf ID
values for all the files that comprise the Study Report. The subsequent STF would
contain only references to the additional leaf elements being included. The operation
attribute value of the leaf element for the subsequent STF should be "append" and the
modified-file attribute of that leaf element should reference the most recently submitted
STF leaf element for that study in that eCTD element. The study-document information
provided in this subsequent STF should only relate to what is being added in the current
submission relative to the last submission for the same STF.
For example, when an STF is being submitted in a subsequent sequence to provide

additional components (additions, corrections, updates, etc.) to update information in the
existing STF (e.g., original STF provided in sequence 0000), the index.xml file of the
subsequent sequence would contain the following leaf entry:
<m4-2-1-1-primary-pharmacodynamics>
Page 10
<leaf checksum-type="MD5"
version="STF version 2.2" xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="append"
xlink:href="m4/42-stud-rep/421-pharmacol/4211-prim-pd/stf-jm-12-345.xml"
modified-file="../0000/index.xml#m12345"
ID="m42111">
<title>jm-12-345 Study Tagging File</title>
</leaf>
</m4-2-1-1-primary-pharmacodynamics>
V. MODIFYING STF INFORMATION
During the lifecycle of an application, modifications to information contained in the STF

might be appropriate as the result of changes to the documentation cited in the STF,
changes to the categorization of information cited in the STF, or to correct errors in a
previous STF.
These modifications can be grouped as:

• changes to the STF study-identifier information and
• changes to the STF study document information.
A. Changes to the STF Study Identifier Information
When an applicant determines that Study Identifier Information was incomplete or

incorrect (for example, a category element value was missing or erroneous in a
previously submitted STF), an STF XML file with the corrected category elements
should be submitted.
For example, an applicant submits the first STF for a single-dose oral toxicity study
(Study No. JM-12-345) in eCTD element 4.2.3.1 in sequence 0001. The index.xml would
contain a leaf entry for this file as follows:
version="stf version 2.2" xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="m4/42-stud-rep/423-tox/4231-single-dose-tox/stf-jm-12-345.xml"
ID="idm42111-0002">
<title>Study No. JM-12-345 STF</title>
</leaf>
The study-identifier section of this STF contains the following information:
<study-identifier>
<title>Single dose oral toxicity study in the mouse and dog</title>
<study-id>jm-12-345</study-id>
Page 11
<category name = "species" info-type = "ich">rat</category>

<category name = "species" info-type = "ich">dog</category>
<category name = "route-of-admin" info-type = "ich">oral</category>
</study-identifier>
Clearly, the species identified by the species category tags are incorrect.
To correct this information, the applicant would submit a corrected STF in a subsequent
sequence. As there is no mechanism for comparing the information contained in the
study-identifier sections of the STFs submitted over time, the information contained in
the study-identifier section of the most recent STF will be deemed the most current. This
applies to all information contained in the study-identifier section of the STF (title, study-
id and category tags).
In order to correct the study-identifier information cited above for Study JM-12-345, an
additional STF would be submitted, appended to the most recent STF, containing the
corrected information.
The index.xml in this subsequent sequence (0002) would contain a leaf for the new STF
as follows:
version="stf version 2.2" xlink:type="simple"
modified-file="../0001/index.xml#idm42111-0002"
ID="a345">
<title>Study No. JM-12-345 STF</title>
</leaf>
If there was no additional documentation being provided for this study (and thus the
purpose of this STF is solely to correct the erroneous study-identifier information), the
STF would contain the following:

<?xml-stylesheet type="text/xsl" href="../../../util/style/ich-stf-stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<category name="species" info-type="ich">mouse</category>
<category name="species" info-type="ich">dog</category>
<category name="route-of-admin" info-type="ich">oral</category>
</study-identifier>
<study-document/>
</ectd:study>
Page 12
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.
Note: The entire study-identifier block should be resubmitted containing all the category
values. The <study-document/> indicates that no additional file-tags are being provided and
is technically required since the study-document element is a technically mandatory element.
B. Changes to STF Study Document Information
During the lifecycle of an application, modifications to the Study Document Information

contained in the STF might be called for as a result of changes to the documentation cited
in the STF, changes to the categorization of documents cited in the STF, or to correct
errors in a previous STF.
These modifications can be grouped as:

1. Adding leaf element references into an existing STF,
2. Deleting leaf elements cited in an existing STF, and
3. Correcting file-tag values for leaf elements cited by an existing STF.
1. Adding New Files to an Existing STF

To add leaf element references into an existing STF, the applicant should submit a
subsequent STF referencing the leaf elements to be added to the existing STF. The
index.xml for this sequence would contain a leaf element for the STF and additional leaf
elements for any new files being provided in that sequence. The operation attribute value
of the leaf element for the STF should be submitted with the ‘append’ operation and
should modify the most recent STF for the study in that eCTD element. The operation
attribute value for any additional leaf elements is dependent on the specific life cycle
situation for that leaf element and would have an operation attribute value of new, append
or replace.
2. Deleting Files Cited by an Existing STF

When a leaf element reference is to be deleted from an STF, a subsequent STF should not
be submitted. The index.xml for this sequence should contain a leaf element with an
operation attribute of "delete" referencing the leaf element to be deleted. No additional
STF file would be called for since the leaf element for the file will be flagged as deleted
and is thus effectively removed from the current view of the leaf elements referenced by
the STF in that eCTD element.
3. Correcting File-tag Values

When an applicant determines that an incorrect file-tag value has been assigned to a study
report component file in the STF, the applicant should "delete" the incorrectly tagged leaf
element in the index.xml (to effectively remove the leaf element from any STF
referencing it as it would no longer be current) and then reactivate the file in the
backbone by including a second leaf with the operation value "new". The file does not
need to be resubmitted; the reactivating xlink:href attribute points back to the original
location of the file.
Page 13
Then, an STF referencing this new leaf entry should be submitted with the corrected file
tag value.
In the following example the applicant inadvertently tagged the synopsis file as a legacy-
clinical-study-report in sequence 0000 and corrects the error in sequence 0003.
In the sequence 0000 index.xml,
xlink:type="simple"
xlink:href="m4/42-stud-rep/423-tox/4231-single-dose-tox/synopsis-of-jm-12-345.pdf"
application-version="PDF 1.4"
ID="m42111">
<title>jm-12-345 Study Synopsis</title>
</leaf>
xlink:type="simple"
version="stf version 2.2"
ID="m42112">
<title>Study JM-12-345 STF</title>
</leaf>
In the sequence 0000 stf-jm-12-345.xml file
<study-document>
<doc-content xlink:href = "../../../index.xml#m42111">
<file-tag name = "legacy-clinical-study-report" info-type = "ich"/>
</doc-content>
</study-document>
To correct the file-tag error, the following actions would be taken.
In the sequence 0003 index.xml, delete the incorrect file-tag by deleting the leaf element
from the index.xml which logically deletes the legacy-clinical-study-report file-tag
associated with it in the STF:
<leaf operation="delete"
checksum="" checksum-type="MD5"
ID="idm4211stf">
<title/>
</leaf>
Page 14
Then, resubmit a leaf element for the file with an operation attribute value of "new"
citing the location of the file in the 0000 sequence - there is no need to send a second
copy of the file:
xlink:type="simple"
xlink:href="../0000/m4/42-stud-rep/423-tox/4231-single-dose-tox/synopsis-of-jm-12-
345.pdf"
<title>jm-12-345 Study Synopsis</title>
ID="r34567">
</leaf>
Finally, include another STF (using the "append" operation) and associate the correct
synopsis file-tag to the file.
xlink:type="simple"
version="stf version 2.2" ID="r6789">
<title>Study JM-12-345 STF</title>
</leaf>
In the sequence 0003 STF for JM-12-345, include the study-id tag to identify the study
report being modified and include the corrected file-tag metadata:

<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet.xsl"?>
<study-identifier>
<category name="species" info-type="ich">mouse</category>
<category name="species" info-type="ich">dog</category>
<category name="route-of-admin" info-type="ich">oral</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../index.xml#r34567">
<file-tag name="synopsis" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Page 15
VI. STUDY DATA MANAGEMENT OPTIONS
In most situations, one study would generate one STF and the information generated from
the study would reside together with the STF in the most appropriate subsection of the
CTD. However, there are certain situations where one study could generate more than
one STF representation. These situations might exist where:
• different analyses with distinct life-cycle management needs co-exist and should
be distinguishable within the same eCTD section of the dossier
• a study generates information that should be presented in a different subsection of
the CTD.
A. Distinguishing Time-Specific Analyses Within the Same Subsection of the

CTD
In certain instances, the reporting of results can best be managed by maintenance
of more than one STF for the same study. This situation generally arises when
unique time point analyses (i.e. the latter analysis does not replace the earlier
analysis) have their own life-cycle management needs, and thus are better kept as
distinct reviewable units.
For example, in studies where patients continue to be followed and reported on

(with or without active dosing) beyond the official, protocol-defined, efficacy
and/or safety endpoints, the subsequent safety, efficacy or relapse analysis
supports a different clinical purpose than the earlier analysis and thus should not
replace or append the earlier analysis.
This can be illustrated through consideration of a study with protocol-defined

specific time point analyses (perhaps through a Drug Safety Monitoring Board)
that are required by each region to be submitted and reviewed to continue the
study. Thus, in one sequence, the Applicant provides safety and efficacy data for
the subset of patients with 12 weeks of exposure at that point in time. While this
information is being reviewed, the Applicant submits patient data from 18 weeks
of exposure as well as updates the 12-week database with the additional patients
who have achieved that length of exposure. In this instance, it would not be
considered appropriate to replace the 12-week data with the 18-week data. These
two sets of data should be kept as distinct, reviewable units of information with
their own lifecycle management needs.
B. Presenting Information from One Study in a Different Subsection of the

CTD
Some studies generate data supporting more than one section of the CTD. A
standard mechanism for placing this information in the appropriate CTD sections
should be available. For example, a safety and/or efficacy study might also have a
‘secondary purpose’ to perform a pharmacokinetic evaluation on all or some of
the patients in that study.
Page 16
Filing all of this information (separate sets of analysis and supportive appendices
and datasets) under just one section of the dossier is generally considered
unsatisfactory, as there would be no method to associate the ‘secondary’
information to the proper section of the CTD. An approach might be to include
the same “all-inclusive” STF in both locations to alert the reviewers that there is
information contained in the STF applicable to more than one section of the CTD.
However, this creates an additional burden on the reviewer in identifying which
datasets, listings and appendices are relevant to the PK assessment and which are
relevant to the full safety/efficacy analysis.
Thus, an applicant has the optional ability to organize these different sets of
information as discrete units by creating a second STF for the same study.
Information that is shared by the two analyses (e.g., protocol, Case Report Form)
would be referenced by each STF while information that supports different
sections of the dossier could be clearly organized and submitted in the appropriate
CTD section. This is especially beneficial to applicants preparing two distinct
study reports for the study (one presenting the safety/efficacy analysis on all
patients and one presenting the pharmacokinetic analysis on the subset of patients
who participated in that part of the study).
Before submitting information of this nature you are advised to consult regional
guidance for how best to present this data.
VII. EXAMPLE SCENARIO
This section provides a series of sample sequences related to the same study.
Sequence 0000
An applicant is providing information on a placebo-controlled study in the treatment of
nausea titled "Wonderdrug Study S107" performed under their in-house unique
identification "S107". In sequence number 0000, the applicant provides interim study
results in the form of an interim synopsis, the body of the interim study report and the
protocol for the study.
The index.xml for sequence 0000 would contain four leaf entries, one for each content
file and one for the STF for the study as follows:
<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-
indication>
xlink:type="simple"
xlink:href="m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-rep-
contr/study-s107/synopsis.pdf"
ID="a101">
Page 17
<title>S107 Study Synopsis - Interim Results</title>

</leaf>
xlink:type="simple"
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="new"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-rep-
contr/study-s107/study-report-body.pdf"
ID="a102">
<title>S107 Study Report Body - Interim Results</title>
</leaf>
xlink:type="simple"
checksum="98723f7594b5500a861509547c384e46" operation="new"
contr/study-s107/protocol.pdf"
ID="a103">
<title>S107 Study Protocol</title>
</leaf>
xlink:type="simple"
checksum="25d3b246313a9dbf688a48da2295260e" operation="new"
contr/study-s107/stf-s107.xml"
ID="a104">
<title>Study Tagging File for S107</title>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-
indication>
The STF provided in sequence 0000 is named "stf-s107.xml" and contains the following
information about the documentation being provided for study S107:

<study-identifier>
<title>Wonderdrug Study S107</title>
<study-id>S107</study-id>
<category name="type-of-control" info-type="ich">no-treatment</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#a101">
</doc-content>
Page 18
<file-tag name="study-report-body" info-type="ich"/>
</doc-content>
<file-tag name="protocol-or-amendment” info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Note: The type of control for this study was intentionally cited as “no-treatment” even
though the study is a placebo-controlled study. This will be corrected in a subsequent
submission (see sequence 0002).
Sequence 0001
In a subsequent submission, the sponsor wishes to provide additional documentation on
Study S107. In sequence 0001, the Sponsor provides the Sample Case Report Form and a
protocol amendment.
The index.xml for sequence 0001 would contain three leaf entries, one for each content
file (i.e., the protocol amendment and the Sample CRF) and one for the STF which
updates the previously submitted STF as shown here:
indication>
xlink:type="simple"
contr/study-s107/protamend01.pdf"
ID="a567">
<title>S107 Protocol Amendment No. 1</title>
</leaf>
xlink:type="simple"
contr/study-s107/samplecrf.pdf"
ID="a568">
<title>S107 Sample Case Report Form</title>
</leaf>
xlink:type="simple"
checksum="25d3b246313a9dbf688a48da2295260e" operation="append"
Page 19
ID="a569">
</leaf>
indication>
The new STF is also named "stf-s107.xml" and summarizes only the new information
being provided in this submission as follows:

<study-identifier>
<category name="type-of-control" info-type="ich">no-treatment</category>
</study-identifier>
<study-document>
<file-tag name="protocol-or-amendment" info-type="ich"/>
</doc-content>
<file-tag name="sample-case-report-form" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Note: The type of control for this study was intentionally cited as “no-treatment” even
though the study is a placebo-controlled study. This will be corrected in a subsequent
submission (see sequence 0002).
Sequence 0002
In a subsequent submission, the sponsor wishes to provide additional documentation on
Study S107. In sequence 0002, the Sponsor provides the final study report and synopsis
plus CRF files for two patients who died during the conduct of the study. In addition, it
was finally noticed that the previous STFs had incorrectly identified the study as an
uncontrolled study when, in fact, it was placebo-controlled.
Page 20
The index.xml for sequence 0002 would contain five leaf entries, one for each content
file (i.e., synopsis, study report and two patient CRF files) and one for the STF which
would append the most recent STF as shown here:
indication>
xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="replace"
contr/study-s107/synopsis.pdf"
ID="r345">
<title>S107 Study Synopsis - Final</title>
</leaf>
xlink:type="simple"
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="replace"
contr/study-s107/s107body.pdf"
ID="r346">
<title>S107 Study Report - Final</title>
</leaf>
xlink:type="simple"
contr/study-s107/crf/11/12.pdf"
ID="r347">
<title>CRF for Subject S107-11-12</title>
</leaf>
xlink:type="simple"
contr/study-s107/crf/162/5045.pdf"
ID="r348">
<title>CRF for Patient S107-162-5045</title>
</leaf>
xlink:type="simple"
checksum="25d3b246313a9dbf688a48da2295260e" operation="append"
Page 21

ID="r349">
</leaf>
indication>
The new STF is named "stf-s107.xml" and identifies the additional documentation
provided for Study S107 in this submission. The information in this STF also corrects the
erroneous “type-of-control” category tag to “placebo” as follows:

<study-identifier>
<category name="type-of-control" info-type="ich">placebo</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#r345">
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r346">
<file-tag name="study-report-body" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r347" >
<property name="site-identifier" info-type="us">11</property>
<file-tag name="case-report-forms" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r348" >
<property name="site-identifier" info-type="us">162</property>
<file-tag name="case-report-forms" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Page 22
FDA Portable Document Format (PDF) Specifications
FDA PORTABLE DOCUMENT FORMAT (PDF) SPECIFICATIONS
Revision History
Date Summary of Changes Version

2005-04-08 Initial version 1.0
2008-06-04 Changed “Bookmarks and Page” 2.0
to “Bookmarks Panel and Page”
in Open Dialog Box section
2011-12-20 Updated to align with ICH 3.0
recommendation on PDF version
1.7; add “Purpose” section; clarify
specifications related to security,
usability, and promotional
materials; revise list of standard
fonts; add PDF optimization; and
incorporate editorial changes
2012-1-20 Clarified language on acceptable 3.1
PDF versions for documents;
added page numbers
Version 3.1 1
FDA PORTABLE DOCUMENT FORMAT (PDF) SPECIFICATIONS
PURPOSE
These specifications are for submitting documents in Portable Document Format (PDF). The purpose of this
document is to provide specifications for submitting PDF files that align with the ICH M2
recommendations 1 and that are in a format that the receiving Center currently supports. For purposes of this
document, “supports” means the receiving Center has established processes and technology infrastructure to
support the receipt, processing, review, and archive of files in the specified standard format. PDF is an
open, published format created by Adobe Systems Incorporated (http://www.adobe.com). Software from a
variety of sources can be used to create files in the PDF format.
VERSION
PDF versions 1.4 through 1.7 are acceptable. Submitted PDF files should be readable by Adobe Acrobat 8.0,
should not require additional software or plug-ins to be read and navigated, and should be text searchable. If
plug-ins are used during the creation of a PDF document, prior to submitting the document, ensure that a
plug-in is not needed for review or archive.
SECURITY
Do not activate security settings or password protection. The integrity of the submitted files is maintained
through Agency security and archival processes. A copy of the files, generated from the submitted files, will
be provided to the reviewer. The reviewer should be able to print, select text and graphics, and make
changes to text, notes and form fields using the provided copy.
FDA Forms downloaded from the FDA Forms website contain security settings that prevent changing the
documents. These forms should be submitted as provided, with no additional security added and without
removing the provided security settings.
FONTS
Embed all fonts. PDF viewing software automatically substitutes a font to display text if the font used to
create the text is unavailable on the reviewer’s computer. In some cases, font substitution can occur even
when the fonts are available. For example, Helvetica or Times are substituted even if available on the
reviewer’s computer. Font substitution can affect a document’s appearance and structure, and in some cases
it can affect the information conveyed by a document. Font availability to the reviewer is ensured if all fonts
are embedded. When fonts are embedded, all characters for the font should be included not just a subset of
the fonts being used in the document. Inspect documents to make sure all fonts are fully embedded prior to
submission.
Font embedding does not always solve the problems that occur when a reviewer tries to copy and paste text
from a PDF document into another software format. If the font is not available on the reviewer’s computer,
font substitution results, even if the fonts are embedded. This problem is avoided if the fonts are restricted to
those listed in Table 1.
1
ICH has adopted the use of ISO 32000-1 without extensions and with the following restrictions – PDF files must not
contain: JavaScript; dynamic content which can include audio, video or special effects and animations; attachments; or
3D content. See http://estri.ich.org/recommendations/PDF_V2_0.pdf
Version 3.1 2
Table 1: List of Standard Fonts

Font type Font name
Sans Serif Arial
Arial Italic
Arial Bold
Arial Bold Italic
Non Proportional Courier New
Courier New Italic
Courier New Bold
Courier New Bold Italic
Serif Times New Roman
Times New Roman Italic
Times New Roman Bold
Times New Roman Bold Italic
Other Symbol
Zapf Dingbats
Use font sizes ranging from 9 to 12 point. Times New Roman 12-point font is recommended for narrative
text. When choosing a point size for tables, a balance should be made between providing sufficient
information on a single page that may facilitate data comparisons while still achieving a point size that
remains legible. Generally, point sizes 9-10 are recommended for tables; smaller point sizes should be
avoided. Ten point fonts are recommended for footnotes.
Black is the recommended font color except that blue can be used for hypertext links. Light colors do not
print well on grayscale printers. Any colors used should be tested prior to submission by printing sample
pages from the document using a grayscale printer.
PAGE ORIENTATION
Save the page orientation for proper viewing and printing within the document. Proper page orientation
eliminates the need for reviewers to rotate pages. For example, setting page orientation of landscape pages to
landscape prior to saving the PDF document in final form ensures a correct page presentation.
PAGE SIZE AND MARGINS
Set up the print area for pages to fit on a sheet of paper that is 8.5 inches by 11 inches. A margin of at least
3/4 of an inch on the left side of page avoids obscuring information when pages are subsequently printed and
bound. Setting the margin for at least 3/8 of an inch on the other sides is sufficient. For pages in landscape
orientation, a margin of 3/4 of an inch at the top allows more information to be displayed legibly on the
page. Header and footer information should not invade the specified margins (i.e., header and footer
information should not appear within 3/8 of an inch of the edge of the 8.5 by 11 inch page), so the text will
not be lost upon printing or being bound. These margins allow printing on A4 as well. Oversized documents
(e.g., CAD drawings or other specialized documents) and promotional materials submitted in PDF format
should be created according to their actual page size.
Version 3.1 3
SOURCE OF ELECTRONIC DOCUMENTS
Avoid image-based PDF files whenever possible. PDF documents produced by scanning paper documents
usually have poorer image resolution than PDF documents produced from electronic source documents such
as word processing files. Scanned documents are generally more difficult to read and do not allow the
reviewer to search or copy and paste text for editing in other documents. If scanned files must be submitted,
they should be made text searchable where possible. If optical character recognition software is used, verify
that imaged text is converted completely and accurately.
METHODS FOR CREATING PDF DOCUMENTS AND IMAGES
Use the dpi settings in Table 2 for scanning documents. Scanned documents scanned at a resolution of 300
dots per inch (dpi) ensure that the pages of the document are legible both on the computer screen and when
printed and, at the same time, minimizes the file size. The use of grayscale and color significantly increases
the file size and should be used only when these features improve the reviewability of the material. After
scanning, avoid resampling to a lower resolution. A captured image should not be subjected to non-uniform
scaling (i.e., sizing). See the following table for resolutions for various images.
Table 2: Scanning Resolution

Document type Resolution
Handwritten notes 300 dpi (black ink)
Plotter output graphics 300 dpi
Photographs – black and white 600 dpi (8 bit gray scale)
Photographs – color 600 dpi (24 bit RGB)
Gels and karyotypes 600 dpi (8 bit grayscale depth)
High pressure liquid chromatography 300 dpi
IMAGE COMPRESSION TO REDUCE FILE SIZE
Compress files using either Zip/Flate or CCITT Group 4. File compression is a method for reducing file size.
Some methods of compression can result in loss of data and can introduce compression artifacts that affect
the reviewability of the information. The following two methods provide lossless compression.
 Zip/Flate (one technique with two names) for lossless compression of color and grayscale images is
specified in Internet RFC 1950 and RFC 1951.
 CCITT Group 4 Fax compression technique recommendations for lossless compression of black and
white images is specified in T.6 (1988) - Facsimile coding schemes and coding control functions for
Group 4 facsimile apparatus.
OPTIMIZE FOR FAST WEB VIEW
Create files from source documents using the “Optimize the PDF for fast web view” option to reduce file
sizes and file opening times.
IMAGE COLOR MATCHING
Because color varies from monitor to monitor, it is difficult to ensure that the reviewer will see exactly the
same color as in the actual image. However, for printing, there is more control over the color by using
CMYK (Cyan, Magenta, Yellow, Black) color model as opposed to the RGB model. Pantone Matching
Version 3.1 4
using the color profile provided by CMYK ensure color consistency for printing. The International Color
Consortium (ICC) 2 color profile specification is used when PDF documents are printed.
USE OF THUMBNAILS
PDF documents do not need embedded thumbnails.
HYPERTEXT LINKING AND BOOKMARKS IN TEXT AND TABLE OF CONTENTS
Hypertext links and bookmarks improve navigation through PDF documents. Use hypertext links throughout
the body of the document to link to supporting annotations, related sections, references, appendices, tables,
or figures that are not located on the same page as the narrative text. Hypertext links in text can be
designated by rectangles using thin lines or by blue text. A consistent method of designating links in a
document avoids confusion. Using relative paths when creating hypertext links minimizes the loss of
hyperlink functionality when submissions are loaded onto network servers. Both absolute links that
reference specific drives and links to root directories do not work once the submission is loaded.
The document table of contents helps the reviewer navigate to the information of interest within the
document that is not provided in the submission table of contents. For documents with a table of contents,
provide bookmarks and hypertext links for each item listed in the table of contents including all tables,
figures, publications, other references, and appendices that are essential for navigation through documents.
The use of invisible rectangles and blue text in the table of contents for hypertext links avoids obscuring
text. Other help for navigation includes a bookmark hierarchy identical to the table of contents; up to 4
levels deep in the hierarchy.
When creating bookmarks and hyperlinks, set the magnification setting to “Inherit Zoom” so the destination
page displays at the same magnification level that the reviewer is using for the rest of the document.
INITIAL VIEW SETTINGS
Set the Navigation Tab to open to “Bookmarks Panel and Page.” This sets the initial document view when
the file is opened. If there are no bookmarks, set the Navigation Tab to “Page Only.” Page Layout and
Magnification should be set to “Default.”
PAGE NUMBERING
In general, it is easier to navigate through an electronic document if the page numbers for the document and
the PDF file are the same, with the initial page of the document numbered as page one. There is an exception
when a document is split because of its size (e.g., > 100 MB) and the second or subsequent file is numbered
consecutively to that of the first or preceding file.
NAMING PDF FILES
Use lower case characters and avoid using special characters except hyphens and underscores in file names.
Special characters to avoid include punctuation, spaces, or other non-alphanumeric symbols (e.g., \ / : * ? <
> | “ % # +) . The current FDA validation criteria and the ICH eCTD specification both provide additional
guidance on allowable special characters in file names.
2
http://www.color.org/
Version 3.1 5
SPECIAL CONSIDERATIONS FOR PROMOTIONAL MATERIAL
Promotional materials submitted in PDF format may need special consideration to ensure accurate
representation of the actual image. Since color varies from monitor to monitor, it is difficult to ensure that
the reviewer will see exactly the same color as in the actual image. Provide images at the highest resolution
and depth practical. For photographs, the image should be obtained with a resolution of at least 600 dpi.
Documents that are available only in paper should be scanned at resolutions that will ensure the pages are
legible both on the computer monitor and when printed; at least 600 dpi is recommended. Promotional
material should be submitted according to its actual size when practical. When an image size is altered, the
original dimensions must be stated. Images of three-dimensional promotional pieces must show all sides
and components.
Version 3.1 6

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The eCTD Backbone Files Specification for Module 1

The eCTD BACKBONE FILES SPECIFICATION FOR MODULE 1

TABLE OF CONTENTS ....................................................................................................................... 1

List of In-Text tables

• Bold italic font is used for elements and attributes.

Table 1: Attribute List Table

II. START OF THE MODULE 1 eCTD BACKBONE FILE

• Version of XML being used

The common header is provided below:

<?xml version="1.0" encoding="UTF-8" standalone="no"?>

III. ADMIN ELEMENTS

Provide this element with every submission.

• The information in the submission-description element should be a high level description of

• Some examples of helpful submission descriptions are listed below:

• Supplement provides for new manufacturing site

• The field should not:

An example of the applicant-contacts element containing two applicant-contact elements is shown

Each application element has a required attribute of application-containing-files and requires a

The elements contained in the application element are application-information and

Provide the six (6)-digit application number in the cross-reference-application-number element.

Each cross-reference-application-number element requires an attribute of application-type and the

The following is an example of a cross-reference-application-number element. In this example, the

a. Submission-id element - <submission-id>

The submission-id element contains two attributes: submission-type and supplement-effective-date-

Below is an example of a submission-id element for a labeling supplement to an application. This

b. Sequence-number Element - <sequence-number>

c. Form Element - <form>

Table 2: Submission Types and Descriptions of Use

Table 3: Supplement-Effective-Date-Types and Descriptions of Use

Table 4: Submission Sub-Types and Descriptions of Use

Amendment A submission that contains additional supportive Original Application,

Submission Valid For the Listed

3. Building Regulatory Activities

submission-sub-type attribute fdasst3 (application)

Table 6: Building Regulatory Activities – Scenario 2

IV. Grouped Submissions

Table 7: Grouped Submissions Limitations and Use

Table 8: Grouped Submission – Scenario 1

Table 9: Grouped Submission – Scenario 2

VI. SECTION HEADING ELEMENTS FOR MODULE 1

A. M1 Regional Section Headings Requiring Attributes

Table 10: Form Types and eCTD Location

C. Module 1.15 — Promotional Material

In the example below, the promotional-material-audience-type indicates the promotional material is

Table 11: Promotional Material Audience Types and Descriptions

Table 12: Promotional Material Doc Types and Descriptions

Promotional Material Description

dissemination/publication as required by 21 CFR 314.550 and 601.45

Table 13: Material ID and Issue Date Descriptions

Material ID The applicant's identification code or other designation of the

APPENDIX 1: M1 Document Type Definition (DTD) Version 3.3

xlink:show (embed | none | other | new | replace) #IMPLIED

xml:lang CDATA #IMPLIED

<!ELEMENT m1-6-meetings (m1-6-1-meeting-request*, m1-6-2-meeting-background-

xml:lang CDATA #IMPLIED

<!ELEMENT m1-13-1-summary-for-nonclinical-studies ((leaf | node-extension)*)>

xml:lang CDATA #IMPLIED

<!ELEMENT m1-14-3-listed-drug-labeling (m1-14-3-1-annotated-comparison-with-listed-

xml:lang CDATA #IMPLIED