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.
ICH eCTD Specification V 3.2.2 16-July-2008
Document Change History
Version
Number
Date Description
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 V 3.2.2 16-July-2008
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
ICH eCTD Specification V 3.2.1 16-July-2008
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 V 3.2.2 16-July-2008
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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:
ICH eCTD Specification V 3.2.2 16-July-2008
Page
2
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.
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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.
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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.
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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 2-2
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:
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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)
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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, 3
rd
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
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[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
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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.
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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
CTD
Description Folder Name
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
Summaries
26-nonclin-sum
2.7 Clinical summary 27-clin-sum
A representative folder hierarchy for module 2 is presented in the screenshot in figure 3-1.
Page 3-3
Figure 3-1 Screenshot representation of the folder structure of module 2
Page 3-4
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
Section in
CTD
Description Folder Name
3.2 Body of Data 32-body-data
3.2.S Drug Substance 32s-drug-sub
3.2.S Drug Substance [Drug Substance Name]
[Manufacturer]
2
substance-1-manufacturer-1
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,
manufacturer)
32s4-contr-drug-sub
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,
manufacturer)
32s43-val-analyt-proc
3.2.S.4.4 Batch Analyses (name, manufacturer) 32s44-batch-analys
3.2.S.4.5 Justification of Specification (name,
manufacturer)
32s45-justif-spec
3.2.S.5 Reference Standards or Materials (name,
manufacturer)
32s5-ref-stand
3.2.S.6 Container Closure System (name,
manufacturer)
32s6-cont-closure-sys
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
Product (name, dosage form)
32p1-desc-comp
3.2.P.2 Pharmaceutical Development (name, dosage
form)
32p2-pharm-dev
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 3-5
Section in
CTD
Description Folder Name
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,
dosage form)
32p53-val-analyt-proc
3.2.P.5.4 Batch Analyses (name, dosage form) 32p54-batch-analys
3.2.P.5.5 Characterisation of Impurities (name, dosage
form)
32p55-charac-imp
3.2.P.5.6 Justification of Specifications (name, dosage
form)
32p56-justif-spec
3.2.P.6 Reference Standards or Materials (name, dosage
form)
32p6-ref-stand
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,
dosage form, manufacturer)
32a2-advent-agent
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 3-6
A representative folder hierarchy for module 3 is presented in the screenshot in figure 3-2.
Figure 3-2 Screenshot representation of the folder structure of module 3
Page 3-7
Module 4 Nonclinical Study Reports
The name of the folder for module 4 should be m4. The folders in module 4 should be named as follows but
can be further reduced or omitted to minimize path length issues.
Table 3-4
Section in
CTD
Description Folder Name
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
4.2.2.1
Analytical Methods and Validation Reports (if
separate reports are available)
4221-analyt-met-val
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
4.2.3.1
Single-Dose Toxicity (in order by species, by
route)
4231-single-dose-tox
4.2.3.2
Repeat-Dose Toxicity (in order by species, by
route, by duration, including supportive
toxicokinetics evaluations)
4232-repeat-dose-tox
4.2.3.3 Genotoxicity 4233-genotox
4.2.3.3.1 In vitro 42331-in-vitro
4.2.3.3.2
In vivo (including supportive toxicokinetics
evaluations)
42332-in-vivo
4.2.3.4
Carcinogenicity (including supportive
toxicokinetics evaluations)
4234-carcigen
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 pharmacokinetics)
42341-lt-stud
Page 3-8
Section in
CTD
Description Folder Name
4.2.3.4.2
Short-or medium-term studies (including range-
finding studies that cannot be appropriately
included under repeat-dose toxicity or
pharmacokinetics)
42342-smt-stud
4.2.3.4.3 Other studies 42343-other-stud
4.2.3.5
Reproductive and Developmental Toxicity
(including range-finding studies and supportive
toxicokinetics evaluations)
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
4.2.3.5.3
Prenatal and postnatal development, including
maternal function
42353-pre-postnatal-dev
4.2.3.5.4
Studies in which the offspring (juvenile
animals) are dosed and/or further evaluated
42354-juv
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
4.3 Literature References 43-lit-ref
A representative folder hierarchy for module 4 is presented in the screenshot in figure 3-3.
Page 3-9
Figure 3-3 Screenshot representation of the folder structure of module 4
Page 3-10
Module 5 Clinical Study Reports
The name of the folder for module 5 should be m5. The folders in module 5 should be named as follows but
can be further reduced or omitted to minimize path length issues.
Table 3-5
Section in
CTD
Description Folder Name
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
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.1.2
Comparative BA and Bioequivalence (BE)
Study Reports
5312-compar-ba-be-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.1.3 In vitro – In vivo Correlation Study Reports 5313-in-vitro-in-vivo-corr-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.1.4
Reports of Bioanalytical and Analytical
Methods for Human Studies
5314-bioanalyt-analyt-met
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.2
Reports of Studies Pertinent to
Pharmacokinetics using Human Biomaterials
532-rep-stud-pk-human-biomat
5.3.2.1 Plasma Protein Binding Study Reports 5321-plasma-prot-bind-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
Page 3-11
Section in
CTD
Description Folder Name
5.3.2.2
Reports of Hepatic Metabolism and Drug
Interaction Studies
5322-rep-hep-metab-interact-stud
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.2.3
Reports of Studies Using Other Human
Biomaterials
5323-stud-other-human-biomat
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.3
Reports of Human Pharmacokinetic (PK)
Studies
533-rep-human-pk-stud
5.3.3.1
Healthy Subject PK and Initial Tolerability
Study Reports
5331-healthy-subj-pk-init-tol-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.3.2
Patient PK and Initial Tolerability Study
Reports
5332-patient-pk-init-tol-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.3.3 Intrinsic Factor PK Study Reports 5333-intrin-factor-pk-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.3.4 Extrinsic Factor PK Study Reports 5334-extrin-factor-pk-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.3.5 Population PK Study Reports 5335-popul-pk-stud-rep
"Study Report 1" study-report-1
Page 3-12
Section in
CTD
Description Folder Name
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.4
Reports of Human Pharmacodynamic (PD)
Studies
534-rep-human-pd-stud
5.3.4.1 Healthy Subject PD and PK/PD Study Reports 5341-healthy-subj-pd-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.4.2 Patient PD and PK/PD Study Reports 5342-patient-pd-stud-rep
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.5 Reports of Efficacy and Safety Studies
535-rep-effic-safety-stud
5.3.5
Reports of Efficacy and Safety Studies –
Indication Name
indication-1
5.3.5.1
Study Reports of Controlled Clinical Studies
Pertinent to the Claimed Indication
5351-stud-rep-contr
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.5.2 Study Reports of Uncontrolled Clinical Studies 5352-stud-rep-uncontr
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.5.3
Reports of Analyses of Data from More than
One Study
5353-rep-analys-data-more-one-stud
"Study Report 1" study-report-1
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.5.4 Other Study Reports 5354-other-stud-rep
"Study Report 1" study-report-1
Page 3-13
Section in
CTD
Description Folder Name
"Study Report 2" study-report-2
"Study Report 3" study-report-3
5.3.6 Reports of Postmarketing Experience 536-postmark-exp
5.3.7
Case Report Forms and Individual Patient
Listings
6
537-crf-ipl
“Study Report 1” study-report-1
“Study Report 2” study-report-2
“Study Report 3” study-report-3
5.4 Literature References 54-lit-ref
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 3-14
A representative folder hierarchy for module 5 is presented in the screenshot in figure 3-4.
Figure 3-4 Screenshot representation of the folder structure of module 5
Page 3-15
Figure 3-4 Screenshot representation of the folder structure of module 5 (cont)
Page 3-16
Figure 3-4 Screenshot representation of the folder structure of module 5 (cont)
Page 4-1
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:
Each item in the table has a unique sequentially assigned reference number. These reference numbers can
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
Sequential
number
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 4-2
Table 4-1
Number
Title
Element
File index.xml
1
Comment This is the Backbone
Number
Title
Element
File index-md5.txt
2
Comment The MD5 of the Backbone
Page 4-3
Number 1
Title Administrative Information and Prescribing Information
Element m1-administrative-information-and-prescribing-information
Directory m1
3
Comment Only one of the regional directories is needed
Number
Title
Element
Directory m1/eu
4
Comment
EU directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to regional
guidance for details
Number
Title
Element
Directory m1/jp
5
Comment
Japan directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to
regional guidance for details
Number
Title
Element
Directory m1/us
6
Comment
US directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to regional
guidance for details
Number
Title
Element
Directory m1/xx
7
Comment
xx directory; where xx is a two character country code from ISO-3166-1. In addition to the appropriate regional documents, the regional
xml instance should be located in this folder. Refer to regional guidance for details
Page 4-4
Number 2
Title Common Technical Document Summaries
Element m2-common-technical-document-summaries
Directory m2
8
Comment
Number 2.2
Title Introduction
Element m2-2-introduction
Directory m2/22-intro
9
Comment
Number 2.2
Title Introduction
Element m2-2-introduction
File m2/22-intro/introduction.pdf
10
Comment
Number 2.3
Title Quality Overall Summary
Element m2-3-quality-overall-summary
Directory m2/23-qos
11
Comment
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Overall Summary
Number 2.3
Title Introduction
Element m2-3-introduction
File m2/23-qos/introduction.pdf
12
Comment
Number 2.3.S
Title Drug Substance - Name - Manufacturer
Element m2-3-s-drug-substance
13
File m2/23-qos/drug-substance.pdf
Page 4-5
Comment
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
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
Comment
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Overall Summary
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
File m2/23-qos/appendices.pdf
15
Comment
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Overall Summary
Number 2.3.R
Title Regional Information
Element m2-3-r-regional-information
File m2/23-qos/regional-information.pdf
16
Comment
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Overall Summary
Number 2.4
Title Nonclinical Overview
Element m2-4-nonclinical-overview
Directory m2/24-nonclin-over
17
Comment
Number 2.4
Title Nonclinical Overview
Element m2-4-nonclinical-overview
File m2/24-nonclin-over/nonclinical-overview.pdf
18
Comment
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
the document to these sub-headings.
Page 4-6
Number 2.5
Title Clinical Overview
Element m2-5-clinical-overview
Directory m2/25-clin-over
19
Comment
Number 2.5
Title Clinical Overview
Element m2-5-clinical-overview
File m2/25-clin-over/clinical-overview.pdf
20
Comment
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
the document to these sub-headings.
Number 2.6
Title Nonclinical Written and Tabulated Summaries
Element m2-6-nonclinical-written-and-tabulated-summaries
Directory m2/26-nonclin-sum
21
Comment
Number 2.6.1
Title Introduction
Element m2-6-1-introduction
File m2/26-nonclin-sum/introduction.pdf
22
Comment
Number 2.6.2
Title Pharmacology Written Summary
Element m2-6-2-pharmacology-written-summary
File m2/26-nonclin-sum/pharmacol-written-summary.pdf
23
Comment
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
the document to these sub-headings.
Number 2.6.3
Title Pharmacology Tabulated Summary
Element m2-6-3-pharmacology-tabulated-summary
File m2/26-nonclin-sum/pharmacol-tabulated-summary.pdf
24
Comment Should have further navigation via bookmarks
25 Number 2.6.4
Page 4-7
Title Pharmacokinetics Written Summary
Element m2-6-4-pharmacokinetics-written-summary
File m2/26-nonclin-sum/pharmkin-written-summary.pdf
Comment
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
the document to these sub-headings.
Number 2.6.5
Title Pharmacokinetics Tabulated Summary
Element m2-6-5-pharmacokinetics-tabulated-summary
File m2/26-nonclin-sum/pharmkin-tabulated-summary.pdf
26
Comment Should have further navigation via bookmarks
Number 2.6.6
Title Toxicology Written Summary
Element m2-6-6-toxicology-written-summary
File m2/26-nonclin-sum/toxicology-written-summary.pdf
27
Comment
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
the document to these sub-headings.
Number 2.6.7
Title Toxicology Tabulated Summary
Element m2-6-7-toxicology-tabulated-summary
File m2/26-nonclin-sum/toxicology-tabulated-summary.pdf
28
Comment Should have further navigation via bookmarks
Number 2.7
Title Clinical Summary
Element m2-7-clinical-summary
Directory m2/27-clin-sum
29
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
File m2/27-clin-sum/summary-biopharm.pdf
30
Comment
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
the document to these sub-headings.
Number 2.7.2 31
Title Summary of Clinical Pharmacology Studies
Page 4-8
Element m2-7-2-summary-of-clinical-pharmacology-studies
File m2/27-clin-sum/summary-clin-pharm.pdf
Comment
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
the document to these sub-headings.
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
32
Comment
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
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
‘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
File m2/27-clin-sum/summary-clin-safety.pdf
33
Comment
Typically, this document should consist of a single file. The CTD defines further heading levels and navigation should be provided within
the document to these sub-headings.
Number 2.7.5
Title Literature References
Element m2-7-5-literature-references
File m2/27-clin-sum/literature-references.pdf
34
Comment
Number 2.7.6
Title Synopses of Individual Studies
35
Element m2-7-6-synopses-of-individual-studies
Page 4-9
File m2/27-clin-sum/synopses-indiv-studies.pdf
Comment
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
considered sufficient to provide hyperlinks from the listing of the studies, located here, to the locations of the synopses in Module 5.
Page 4-10
Number 3
Title Quality
Element m3-quality
Directory m3
36
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
Element m3-2-body-of-data
Directory m3/32-body-data
37
Comment
Number 3.2.S
Title Drug Substance
Element m3-2-s-drug-substance
Directory m3/32-body-data/32s-drug-sub
38
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
39
Comment
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.
The ‘substance’ and ‘manufacturer’ attribute values in the backbone should be consistent with that used in the folder name but can be
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.
Number 3.2.S.1 40
Title General Information (name, manufacturer)
Page 4-11
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)
Element m3-2-s-1-1-nomenclature
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/nomenclature.pdf
41
Comment
Number 3.2.S.1.2
Title Structure (name, manufacturer)
Element m3-2-s-1-2-structure
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/structure.pdf
42
Comment
Number 3.2.S.1.3
Title General Properties (name, manufacturer)
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
43
Comment
Number 3.2.S.2
Title
Manufacture (name, manufacturer)
Element m3-2-s-2-manufacture
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf
44
Comment
Number 3.2.S.2.1
Title Manufacturer(s) (name, manufacturer)
Element m3-2-s-2-1-manufacturer
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manufacturer.pdf
45
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)
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
46
Comment
Page 4-12
Number 3.2.S.2.3
Title Control of Materials (name, manufacturer)
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
47
Comment
Number 3.2.S.2.4
Title Controls of Critical Steps and Intermediates (name, manufacturer)
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
48
Comment
Number 3.2.S.2.5
Title Process Validation and/or Evaluation (name, manufacturer)
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
49
Comment
Number 3.2.S.2.6
Title Manufacturing Process Development (name, manufacturer)
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
50
Comment
Number 3.2.S.3
Title Characterisation (name, manufacturer)
Element m3-2-s-3-characterisation
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac
51
Comment
Number 3.2.S.3.1
Title Elucidation of Structure and Other Characteristics (name, manufacturer)
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
52
Comment
Number 3.2.S.3.2
Title Impurities (name, manufacturer)
53
Element m3-2-s-3-2-impurities
Page 4-13
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)
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
54
Comment
Number 3.2.S.4.1
Title Specification (name, manufacturer)
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
55
Comment
Number 3.2.S.4.1
Title Specification (name, manufacturer)
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
56
Comment
Number 3.2.S.4.2
Title Analytical Procedures (name, manufacturer)
Element m3-2-s-4-2-analytical-procedures
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc
57
Comment
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, can be organized.
CTD numbering is not defined below this level (e.g., 3.2.S.4.2.1).
Number
Title
A
nalytical Procedure-1
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
58
Comment
Number
Title
A
nalytical Procedure-2
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-2.pdf
59
Comment
Page 4-14
Number
Title
A
nalytical Procedure-3
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-3.pdf
60
Comment
Number 3.2.S.4.3
Title Validation of Analytical Procedures
Element m3-2-s-4-3-validation-of-analytical-procedures (name, manufacturer)
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc
61
Comment
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, can be organized.
CTD numbering is not defined below this level (e.g., 3.2.S.4.3.1).
Number
Title Validation of Analytical Procedure-1
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
62
Comment
Number
Title Validation of Analytical Procedure-2
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-2.pdf
63
Comment
Number
Title Validation of Analytical Procedure-3
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-3.pdf
64
Comment
Number 3.2.S.4.4
Title Batch Analyses (name, manufacturer)
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
65
Comment
66 Number 3.2.S.4.4
Page 4-15
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)
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
67
Comment
Number 3.2.S.4.5
Title Justification of Specification (name, manufacturer)
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
68
Comment
Number 3.2.S.5
Title Reference Standards or Materials (name, manufacturer)
Element m3-2-s-5-reference-standards-or-materials
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand
69
Comment
Number 3.2.S.5
Title Reference Standards or Materials (name, manufacturer)
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
70
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)
Element m3-2-s-6-container-closure-system
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys
71
Comment
Number 3.2.S.6
Title Container Closure System (name, manufacturer)
Element m3-2-s-6-container-closure-system
72
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys/container-closure-system.pdf
Page 4-16
Comment
Number 3.2.S.7
Title Stability (name, manufacturer)
Element m3-2-s-7-stability
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab
73
Comment
Number 3.2.S.7.1
Title Stability Summary and Conclusions (name, manufacturer)
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
74
Comment
Number 3.2.S.7.2
Title Post-approval Stability Protocol and Stability Commitment (name, manufacturer)
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
75
Comment
Number 3.2.S.7.3
Title Stability Data (name, manufacturer)
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
76
Comment
Number 3.2.P
Title Drug Product (name, dosage form)
Element m3-2-p-drug-product
Directory m3/32-body-data/32p-drug-prod
77
Comment
Number 3.2.P
Title Drug Product (name, dosage form) – Name
Element
m3-2-p-drug-product
78
Directory m3/32-body-data/32p-drug-prod/product-1
Page 4-17
Comment
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.
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)
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
79
Comment
Number 3.2.P.1
Title Description and Composition of the Drug Product (name, dosage form)
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
80
Comment
Number 3.2.P.2
Title Pharmaceutical Development (name, dosage form)
Element m3-2-p-2-pharmaceutical-development
Directory m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev
81
Comment
Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical
Development section.
Number 3.2.P.2
Title Pharmaceutical Development (name, dosage form)
Element m3-2-p-2-pharmaceutical-development
82
File m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev/pharmaceutical-development.pdf
Page 4-18
Comment
Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical
Development section.
Number 3.2.P.3
Title
Manufacture (name, dosage form)
Element m3-2-p-3-manufacture
Directory m3/32-body-data/32p-drug-prod/product-1/32p3-manuf
83
Comment
Number 3.2.P.3.1
Title Manufacturer(s) (name, dosage form)
Element m3-2-p-3-1-manufacturers
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manufacturers.pdf
84
Comment
Number 3.2.P.3.2
Title Batch Formula (name, dosage form)
Element m3-2-p-3-2-batch-formula
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/batch-formula.pdf
85
Comment
Number 3.2.P.3.3
Title Description of Manufacturing Process and Process Controls (name, dosage form)
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
86
Comment
Number 3.2.P.3.4
Title Controls of Critical Steps and Intermediates (name, dosage form)
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
87
Comment
Number 3.2.P.3.5
Title Process Validation and/or Evaluation (name, dosage form)
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
88
Comment The applicant has the option to submit one or multiple files, one for each validation or evaluation.
Page 4-19
Number 3.2.P.4
Title Control of Excipients (name, dosage form)
Element m3-2-p-4-control-of-excipients
Directory m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip
89
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
90
Comment
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
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.
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)
Element m3-2-p-4-1-specifications
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/specifications.pdf
91
Comment See comment under 3.2.P.4.
Number 3.2.P.4.2
Title Analytical Procedures (name, dosage form)
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
92
Comment See comment under 3.2.P.4.
Number 3.2.P.4.3
Title Validation of Analytical Procedures (name, dosage form)
93
Element m3-2-p-4-3-validation-of-analytical-procedures
Page 4-20
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/validation-analyt-procedures.pdf
Comment See comment under 3.2.P.4.
Number 3.2.P.4.4
Title Justification of Specifications (name, dosage form)
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
94
Comment See comment under 3.2.P.4.
Number 3.2.P.4.5
Title Excipients of Human or Animal Origin (name, dosage form)
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
95
Comment
Number 3.2.P.4.6
Title Novel Excipients (name, dosage form)
Element m3-2-p-4-6-novel-excipients
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/novel-excipients.pdf
96
Comment
Number 3.2.P.5
Title Control of Drug Product (name, dosage form)
Element m3-2-p-5-control-of-drug-product
Directory
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod
97
Comment
Number 3.2.P.5.1
Title Specification(s) (name, dosage form)
Element m3-2-p-5-1-specifications
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec
98
Comment
Number 3.2.P.5.1
Title Specification(s) (name, dosage form)
Element m3-2-p-5-1-specifications
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec/specifications.pdf
99
Comment
100 Number 3.2.P.5.2
Page 4-21
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
Comment
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
CTD numbering is not defined below this level (e.g., 3.2.P.5.2.1).
Number
Title
A
nalytical Procedure – 1
Element m3-2-p-5-2-analytical-procedures
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-1.pdf
101
Comment
Number
Title
A
nalytical Procedure – 2
Element m3-2-p-5-2-analytical-procedures
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-2.pdf
102
Comment
Number
Title
A
nalytical Procedure – 3
Element m3-2-p-5-2-analytical-procedures
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-3.pdf
103
Comment
Number 3.2.P.5.3
Title Validation of Analytical Procedures (name, dosage form)
Element m3-2-p-5-3-validation-of-analytical-procedures
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc
104
Comment
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
CTD numbering is not defined below this level (e.g., 3.2.P.5.3.1).
Number
Title Validation of Analytical Procedures – 1
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
105
Comment
Number
106
Title Validation of Analytical Procedures – 2
Page 4-22
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-2.pdf
Comment
Number
Title Validation of Analytical Procedures – 3
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-3.pdf
107
Comment
Number 3.2.P.5.4
Title Batch Analyses (name, dosage form)
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
108
Comment
Number 3.2.P.5.4
Title Batch Analyses (name, dosage form)
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
109
Comment
Number 3.2.P.5.5
Title Characterisation of Impurities (name, dosage form)
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
110
Comment
Number 3.2.P.5.5
Title Characterisation of Impurities (name, dosage form)
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
111
Comment
Number 3.2.P.5.6
Title Justification of Specifications (name, dosage form)
Element m3-2-p-5-6-justification-of-specifications
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec
112
Comment
Page 4-23
Number 3.2.P.5.6
Title Justification of Specifications (name, dosage form)
Element m3-2-p-5-6-justification-of-specifications
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec/justification-of-specifications.pdf
113
Comment
Number 3.2.P.6
Title Reference Standards or Materials (name, dosage form)
Element m3-2-p-6-reference-standards-or-materials
Directory m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand
114
Comment
Number 3.2.P.6
Title Reference Standards or Materials (name, dosage form)
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
115
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)
Element m3-2-p-7-container-closure-system
Directory m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys
116
Comment
Number 3.2.P.7
Title Container Closure System (name, dosage form)
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
117
Comment
Number 3.2.P.8
Title Stability (name, dosage form)
Element m3-2-p-8-stability
Directory m3/32-body-data/32p-drug-prod/product-1/32p8-stab
118
Comment
Number 3.2.P.8.1
Title Stability Summary and Conclusion (name, dosage form)
119
Element m3-2-p-8-1-stability-summary-and-conclusion
Page 4-24
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)
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
120
Comment
Number 3.2.P.8.3
Title Stability Data (name, dosage form)
Element m3-2-p-8-3-stability-data
File m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-data.pdf
121
Comment
Number 3.2.A
Title Appendices
Element m3-2-a-appendices
Directory m3/32-body-data/32a-app
122
Comment
Number 3.2.A.1
Title Facilities and Equipment (name, manufacturer)
Element m3-2-a-1-facilities-and-equipment
Directory m3/32-body-data/32a-app/32a1-fac-equip
123
Comment
Several reports are likely to be included in this appendix. The organisation is left to the applicant to define. However, where there is more
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
Element m3-2-a-1-facilities-and-equipment
File m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-1.pdf
124
Comment
Number
Title Facilities and Equipment Report 2
Element m3-2-a-1-facilities-and-equipment
125
File m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-2.pdf
Page 4-25
Comment
Number
Title Facilities and Equipment Report 3
Element m3-2-a-1-facilities-and-equipment
File m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-3.pdf
126
Comment
Number 3.2.A.2
Title Adventitious Agents Safety Evaluation (name, dosage form, manufacturer)
Element m3-2-a-2-adventitious-agents-safety-evaluation
Directory m3/32-body-data/32a-app/32a2-advent-agent
127
Comment
Nonviral adventitious agents reports should be placed in this folder. For viral adventitious agents the following sub-folder structure should
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
A
dventitious Agents Safety Evaluation Report 1
Element m3-2-a-2-adventitious-agents-safety-evaluation
File m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-1.pdf
128
Comment
Number
Title
A
dventitious Agents Safety Evaluation Report 2
Element m3-2-a-2-adventitious-agents-safety-evaluation
File m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-2.pdf
129
Comment
Number
Title
A
dventitious Agents Safety Evaluation Report 3
Element m3-2-a-2-adventitious-agents-safety-evaluation
File m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-3.pdf
130
Comment
Number 3.2.A.3
Title Excipients Name
Element m3-2-a-3-excipients
131
Directory m3/32-body-data/32a-app/32a3-excip-name-1
Page 4-26
Comment
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'.
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
Element m3-2-r-regional-information
Directory m3/32-body-data/32r-reg-info
132
Comment Refer to the M4 Organisation Document: Granularity Annex for the approach to take with this section.
Number 3.3
Title Literature References
Element m3-3-literature-references
Directory m3/33-lit-ref
133
Comment
Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference). CTD numbering is not defined
below this level (e.g., 3.3.1).
Number
Title Reference 1
Element m3-3-literature-references
File m3/33-lit-ref/reference-1.pdf
134
Comment
Number
Title Reference 2
Element m3-3-literature-references
File m3/33-lit-ref/reference-2.pdf
135
Comment
Number
Title Reference 3
Element m3-3-literature-references
File m3/33-lit-ref/reference-3.pdf
136
Comment
Page 4-27
Number 4
Title Nonclinical Study Reports
Element m4-nonclinical-study-reports
Directory m4
137
Comment
Number 4.2
Title Study Reports
Element m4-2-study-reports
Directory m4/42-stud-rep
138
Comment
Number 4.2.1
Title Pharmacology
Element m4-2-1-pharmacology
Directory m4/42-stud-rep/421-pharmacol
139
Comment
Number 4.2.1.1
Title Primary Pharmacodynamics
Element m4-2-1-1-primary-pharmacodynamics
Directory m4/42-stud-rep/421-pharmacol/4211-prim-pd
140
Comment
Number
Title Study Report 1
Element m4-2-1-1-primary-pharmacodynamics
141
File m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-1.pdf
Page 4-28
Comment
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.
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
Title Study Report 2
Element m4-2-1-1-primary-pharmacodynamics
File m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-2.pdf
142
Comment
Number
Title Study Report 3
Element m4-2-1-1-primary-pharmacodynamics
File m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-3.pdf
143
Comment
Number 4.2.1.2
Title Secondary Pharmacodynamics
Element m4-2-1-2-secondary-pharmacodynamics
Directory m4/42-stud-rep/421-pharmacol/4212-sec-pd
144
Comment
Number
Title Study Report 1
Element m4-2-1-2-secondary-pharmacodynamics
File m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-1.pdf
145
Comment
146 Number
Page 4-29
Title Study Report 2
Element m4-2-1-2-secondary-pharmacodynamics
File m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-2.pdf
Comment
Number
Title Study Report 3
Element m4-2-1-2-secondary-pharmacodynamics
File m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-3.pdf
147
Comment
Number 4.2.1.3
Title Safety Pharmacology
Element m4-2-1-3-safety-pharmacology
Directory m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol
148
Comment
Number
Title Study Report 1
Element m4-2-1-3-safety-pharmacology
File m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-1.pdf
149
Comment
Number
Title Study Report 2
Element m4-2-1-3-safety-pharmacology
File m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-2.pdf
150
Comment
Number
Title Study Report 3
Element m4-2-1-3-safety-pharmacology
File m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-3.pdf
151
Comment
Number 4.2.1.4
Title Pharmacodynamic Drug Interactions
Element
m4-2-1-4-pharmacodynamic-drug-interactions
152
Directory m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact
Page 4-30
Comment
Number
Title Study Report 1
Element m4-2-1-4-pharmacodynamic-drug-interactions
File m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-1.pdf
153
Comment
Number
Title Study Report 2
Element m4-2-1-4-pharmacodynamic-drug-interactions
File m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-2.pdf
154
Comment
Number
Title Study Report 3
Element m4-2-1-4-pharmacodynamic-drug-interactions
File m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-3.pdf
155
Comment
Number 4.2.2
Title Pharmacokinetics
Element m4-2-2-pharmacokinetics
Directory m4/42-stud-rep/422-pk
156
Comment
Number 4.2.2.1
Title Analytical Methods and Validation Reports (if separate reports are available)
Element m4-2-2-1-analytical-methods-and-validation-reports
Directory m4/42-stud-rep/422-pk/4221-analyt-met-val
157
Comment
Number
Title Study Report 1
Element m4-2-2-1-analytical-methods-and-validation-reports
File m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-1.pdf
158
Comment
Number 159
Title Study Report 2
Page 4-31
Element m4-2-2-1-analytical-methods-and-validation-reports
File m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-2.pdf
Comment
Number
Title Study Report 3
Element m4-2-2-1-analytical-methods-and-validation-reports
File m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-3.pdf
160
Comment
Number 4.2.2.2
Title Absorption
Element m4-2-2-2-absorption
Directory m4/42-stud-rep/422-pk/4222-absorp
161
Comment
Number
Title Study Report 1
Element m4-2-2-2-absorption
File m4/42-stud-rep/422-pk/4222-absorp/study-report-1.pdf
162
Comment
Number
Title Study Report 2
Element m4-2-2-2-absorption
File m4/42-stud-rep/422-pk/4222-absorp/study-report-2.pdf
163
Comment
Number
Title Study Report 3
Element m4-2-2-2-absorption
File m4/42-stud-rep/422-pk/4222-absorp/study-report-3.pdf
164
Comment
Number 4.2.2.3
Title Distribution
Element m4-2-2-3-distribution
Directory m4/42-stud-rep/422-pk/4223-distrib
165
Comment
Page 4-32
Number
Title Study Report 1
Element m4-2-2-3-distribution
File m4/42-stud-rep/422-pk/4223-distrib/study-report-1.pdf
166
Comment
Number
Title Study Report 2
Element m4-2-2-3-distribution
File m4/42-stud-rep/422-pk/4223-distrib/study-report-2.pdf
167
Comment
Number
Title Study Report 3
Element m4-2-2-3-distribution
File m4/42-stud-rep/422-pk/4223-distrib/study-report-3.pdf
168
Comment
Number 4.2.2.4
Title Metabolism
Element m4-2-2-4-metabolism
Directory m4/42-stud-rep/422-pk/4224-metab
169
Comment
Number
Title Study Report 1
Element m4-2-2-4-metabolism
File m4/42-stud-rep/422-pk/4224-metab/study-report-1.pdf
170
Comment
Number
Title Study Report 2
Element m4-2-2-4-metabolism
File m4/42-stud-rep/422-pk/4224-metab/study-report-2.pdf
171
Comment
Number
Title Study Report 3
172
Element m4-2-2-4-metabolism
Page 4-33
File m4/42-stud-rep/422-pk/4224-metab/study-report-3.pdf
Comment
Number 4.2.2.5
Title Excretion
Element m4-2-2-5-excretion
Directory m4/42-stud-rep/422-pk/4225-excr
173
Comment
Number
Title Study Report 1
Element m4-2-2-5-excretion
File m4/42-stud-rep/422-pk/4225-excr/study-report-1.pdf
174
Comment
Number
Title Study Report 2
Element m4-2-2-5-excretion
File m4/42-stud-rep/422-pk/4225-excr/study-report-2.pdf
175
Comment
Number
Title Study Report 3
Element m4-2-2-5-excretion
File m4/42-stud-rep/422-pk/4225-excr/study-report-3.pdf
176
Comment
Number 4.2.2.6
Title Pharmacokinetic Drug Interactions (nonclinical)
Element m4-2-2-6-pharmacokinetic-drug-interactions
Directory m4/42-stud-rep/422-pk/4226-pk-drug-interact
177
Comment
Number
Title Study Report 1
Element m4-2-2-6-pharmacokinetic-drug-interactions
File m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-1.pdf
178
Comment
179 Number
Page 4-34
Title Study Report 2
Element m4-2-2-6-pharmacokinetic-drug-interactions
File m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-2.pdf
Comment
Number
Title Study Report 3
Element m4-2-2-6-pharmacokinetic-drug-interactions
File m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-3.pdf
180
Comment
Number 4.2.2.7
Title Other Pharmacokinetic Studies
Element m4-2-2-7-other-pharmacokinetic-studies
Directory m4/42-stud-rep/422-pk/4227-other-pk-stud
181
Comment
Number
Title Study Report 1
Element m4-2-2-7-other-pharmacokinetic-studies
File m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-1.pdf
182
Comment
Number
Title Study Report 2
Element m4-2-2-7-other-pharmacokinetic-studies
File m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-2.pdf
183
Comment
Number
Title Study Report 3
Element m4-2-2-7-other-pharmacokinetic-studies
File m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-3.pdf
184
Comment
Number 4.2.3
Title Toxicology
Element m4-2-3-toxicology
185
Directory m4/42-stud-rep/423-tox
Page 4-35
Comment
Number 4.2.3.1
Title Single-Dose Toxicity (in order by species, by route)
Element m4-2-3-1-single-dose-toxicity
Directory m4/42-stud-rep/423-tox/4231-single-dose-tox
186
Comment
Number
Title Study Report 1
Element m4-2-3-1-single-dose-toxicity
File m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-1.pdf
187
Comment
Number
Title Study Report 2
Element m4-2-3-1-single-dose-toxicity
File m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-2.pdf
188
Comment
Number
Title Study Report 3
Element m4-2-3-1-single-dose-toxicity
File m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-3.pdf
189
Comment
Number 4.2.3.2
Title Repeat-Dose Toxicity (in order by species, by route, by duration, including supportive toxicokinetics evaluations)
Element m4-2-3-2-repeat-dose-toxicity
Directory m4/42-stud-rep/423-tox/4232-repeat-dose-tox
190
Comment
Number
Title Study Report 1
Element m4-2-3-2-repeat-dose-toxicity
File m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-1.pdf
191
Comment
Number 192
Title Study Report 2
Page 4-36
Element m4-2-3-2-repeat-dose-toxicity
File m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-2.pdf
Comment
Number
Title Study Report 3
Element m4-2-3-2-repeat-dose-toxicity
File m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-3.pdf
193
Comment
Number 4.2.3.3
Title Genotoxicity
Element m4-2-3-3-genotoxicity
Directory m4/42-stud-rep/423-tox/4233-genotox
194
Comment
Number 4.2.3.3.1
Title In vitro
Element m4-2-3-3-1-in-vitro
Directory m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro
195
Comment
Number
Title Study Report 1
Element m4-2-3-3-1-in-vitro
File m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-1.pdf
196
Comment
Number
Title Study Report 2
Element m4-2-3-3-1-in-vitro
File m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-2.pdf
197
Comment
Number
Title Study Report 3
Element m4-2-3-3-1-in-vitro
File m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-3.pdf
198
Comment
Page 4-37
Number 4.2.3.3.2
Title In vivo (including supportive toxicokinetics evaluations)
Element m4-2-3-3-2-in-vivo
Directory m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo
199
Comment
Number
Title Study Report 1
Element m4-2-3-3-2-in-vivo
File m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-1.pdf
200
Comment
Number
Title Study Report 2
Element m4-2-3-3-2-in-vivo
File m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-2.pdf
201
Comment
Number
Title Study Report 3
Element m4-2-3-3-2-in-vivo
File m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-3.pdf
202
Comment
Number 4.2.3.4
Title Carcinogenicity (including supportive toxicokinetics evaluations)
Element m4-2-3-4-carcinogenicity
Directory m4/42-stud-rep/423-tox/4234-carcigen
203
Comment
Number 4.2.3.4.1
Title
Long-term studies (in order by species, including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
pharmacokinetics)
Element m4-2-3-4-1-long-term-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud
204
Comment
Number 205
Title Study Report 1
Page 4-38
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
Title Study Report 2
Element m4-2-3-4-1-long-term-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-2.pdf
206
Comment
Number
Title Study Report 3
Element m4-2-3-4-1-long-term-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-3.pdf
207
Comment
Number 4.2.3.4.2
Title
Short- or medium-term studies (including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
pharmacokinetics)
Element m4-2-3-4-2-short-or-medium-term-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud
208
Comment
Number
Title Study Report 1
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
209
Comment
Number
Title Study Report 2
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-2.pdf
210
Comment
Number
Title Study Report 3
Element m4-2-3-4-2-short-or-medium-term-studies
211
File m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-3.pdf
Page 4-39
Comment
Number 4.2.3.4.3
Title Other studies
Element m4-2-3-4-3-other-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud
212
Comment
Number
Title Study Report 1
Element m4-2-3-4-3-other-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-1.pdf
213
Comment
Number
Title Study Report 2
Element m4-2-3-4-3-other-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-2.pdf
214
Comment
Number
Title Study Report 3
Element m4-2-3-4-3-other-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-3.pdf
215
Comment
Number 4.2.3.5
Title
Reproductive and Developmental Toxicity (including range-finding studies and supportive toxicokinetics evaluations) (If modified study
designs are used, the following subheadings should be modified accordingly)
Element m4-2-3-5-reproductive-and-developmental-toxicity
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox
216
Comment
Number 4.2.3.5.1
Title Fertility and early embryonic development
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
217
Comment
218 Number
Page 4-40
Title Study Report 1
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
Title Study Report 2
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-2.pdf
219
Comment
Number
Title Study Report 3
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-3.pdf
220
Comment
Number 4.2.3.5.2
Title Embryo-fetal development
Element m4-2-3-5-2-embryo-fetal-development
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev
221
Comment
Number
Title Study Report 1
Element m4-2-3-5-2-embryo-fetal-development
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-1.pdf
222
Comment
Number
Title Study Report 2
Element m4-2-3-5-2-embryo-fetal-development
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-2.pdf
223
Comment
Number
Title Study Report 3
Element m4-2-3-5-2-embryo-fetal-development
224
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-3.pdf
Page 4-41
Comment
Number 4.2.3.5.3
Title Prenatal and postnatal development, including maternal function
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
225
Comment
Number
Title Study Report 1
Element m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-1.pdf
226
Comment
Number
Title Study Report 2
Element m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-2.pdf
227
Comment
Number
Title Study Report 3
Element m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-3.pdf
228
Comment
Number 4.2.3.5.4
Title Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
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
229
Comment
Number
Title Study Report 1
Element m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-1.pdf
230
Comment
Number 231
Title Study Report 2
Page 4-42
Element m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-2.pdf
Comment
Number
Title Study Report 3
Element m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-3.pdf
232
Comment
Number 4.2.3.6
Title Local Tolerance
Element m4-2-3-6-local-tolerance
Directory m4/42-stud-rep/423-tox/4236-loc-tol
233
Comment
Number
Title Study Report 1
Element m4-2-3-6-local-tolerance
File m4/42-stud-rep/423-tox/4236-loc-tol/study-report-1.pdf
234
Comment
Number
Title Study Report 2
Element m4-2-3-6-local-tolerance
File m4/42-stud-rep/423-tox/4236-loc-tol/study-report-2.pdf
235
Comment
Number
Title Study Report 3
Element m4-2-3-6-local-tolerance
File m4/42-stud-rep/423-tox/4236-loc-tol/study-report-3.pdf
236
Comment
Number 4.2.3.7
Title Other Toxicity Studies (if available)
Element m4-2-3-7-other-toxicity-studies
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud
237
Comment
Page 4-43
Number 4.2.3.7.1
Title Antigenicity
Element m4-2-3-7-1-antigenicity
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen
238
Comment
Number
Title Study Report 1
Element m4-2-3-7-1-antigenicity
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-1.pdf
239
Comment
Number
Title Study Report 2
Element m4-2-3-7-1-antigenicity
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-2.pdf
240
Comment
Number
Title Study Report 3
Element m4-2-3-7-1-antigenicity
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-3.pdf
241
Comment
Number 4.2.3.7.2
Title Immunotoxicity
Element m4-2-3-7-2-immunotoxicity
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox
242
Comment
Number
Title Study Report 1
Element m4-2-3-7-2-immunotoxicity
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-1.pdf
243
Comment
Number
Title Study Report 2
244
Element m4-2-3-7-2-immunotoxicity
Page 4-44
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-2.pdf
Comment
Number
Title Study Report 3
Element m4-2-3-7-2-immunotoxicity
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-3.pdf
245
Comment
Number 4.2.3.7.3
Title Mechanistic studies (if not included elsewhere)
Element m4-2-3-7-3-mechanistic-studies
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud
246
Comment
Number
Title Study Report 1
Element m4-2-3-7-3-mechanistic-studies
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-1.pdf
247
Comment
Number
Title Study Report 2
Element m4-2-3-7-3-mechanistic-studies
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-2.pdf
248
Comment
Number
Title Study Report 3
Element m4-2-3-7-3-mechanistic-studies
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-3.pdf
249
Comment
Number 4.2.3.7.4
Title Dependence
Element m4-2-3-7-4-dependence
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep
250
Comment
251 Number
Page 4-45
Title Study Report 1
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
Title Study Report 2
Element m4-2-3-7-4-dependence
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-2.pdf
252
Comment
Number
Title Study Report 3
Element m4-2-3-7-4-dependence
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-3.pdf
253
Comment
Number 4.2.3.7.5
Title Metabolites
Element m4-2-3-7-5-metabolites
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab
254
Comment
Number
Title Study Report 1
Element m4-2-3-7-5-metabolites
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-1.pdf
255
Comment
Number
Title Study Report 2
Element m4-2-3-7-5-metabolites
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-2.pdf
256
Comment
Number
Title Study Report 3
Element m4-2-3-7-5-metabolites
257
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-3.pdf
Page 4-46
Comment
Number 4.2.3.7.6
Title Impurities
Element m4-2-3-7-6-impurities
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp
258
Comment
Number
Title Study Report 1
Element m4-2-3-7-6-impurities
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-1.pdf
259
Comment
Number
Title Study Report 2
Element m4-2-3-7-6-impurities
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-2.pdf
260
Comment
Number
Title Study Report 3
Element m4-2-3-7-6-impurities
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-3.pdf
261
Comment
Number 4.2.3.7.7
Title Other
Element m4-2-3-7-7-other
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other
262
Comment
Number
Title Study Report 1
Element
m4-2-3-7-7-other
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-1.pdf
263
Comment
Number 264
Title Study Report 2
Page 4-47
Element m4-2-3-7-7-other
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-2.pdf
Comment
Number
Title Study Report 3
Element m4-2-3-7-7-other
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-3.pdf
265
Comment
Number 4.3
Title Literature References
Element m4-3-literature-references
Directory m4/43-lit-ref
266
Comment Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference).
Number
Title Reference 1
Element m4-3-literature-references
File m4/43-lit-ref/reference-1.pdf
267
Comment
Number
Title Reference 2
Element m4-3-literature-references
File m4/43-lit-ref/reference-2.pdf
268
Comment
Number
Title Reference 3
Element m4-3-literature-references
File m4/43-lit-ref/reference-3.pdf
269
Comment
Page 4-48
Number 5
Title Clinical Study Reports
Element m5-clinical-study-reports
Directory m5
270
Comment
Number 5.2
Title Tabular Listing of all Clinical Studies
Element m5-2-tabular-listing-of-all-clinical-studies
Directory m5/52-tab-list
271
Comment
Number 5.2
Title Tabular Listing of all Clinical Studies
Element m5-2-tabular-listing-of-all-clinical-studies
File m5/52-tab-list/tabular-listing.pdf
272
Comment
Number 5.3
Title Clinical Study Reports
Element m5-3-clinical-study-reports
Directory m5/53-clin-stud-rep
273
Comment
Number 5.3.1
Title Reports of Biopharmaceutic Studies
Element m5-3-1-reports-of-biopharmaceutic-studies
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud
274
Comment
Number 5.3.1.1
Title Bioavailability (BA) Study Reports
Element m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep
275
Comment
Number 276
Title Study Report 1
Page 4-49
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
Comment
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
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
Title Study Report 2
Element m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-2
277
Comment
Number
Title Study Report 3
Element m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-3
278
Comment
Number 5.3.1.2
Title Comparative BA and Bioequivalence (BE) Study Reports
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
279
Comment
Number
Title Study Report 1
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/study-report-1
280
Comment
Number
Title Study Report 2
Element m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
281
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep/study-report-2
Page 4-50
Comment
Number
Title Study Report 3
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/study-report-3
282
Comment
Number 5.3.1.3
Title In vitro – In vivo Correlation Study Reports
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
283
Comment
Number
Title Study Report 1
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/study-report-1
284
Comment
Number
Title Study Report 2
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/study-report-2
285
Comment
Number
Title Study Report 3
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/study-report-3
286
Comment
Number 5.3.1.4
Title Reports of Bioanalytical and Analytical Methods for Human Studies
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
287
Comment
Number 288
Title Study Report 1
Page 4-51
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
Title Study Report 2
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-2
289
Comment
Number
Title Study Report 3
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-3
290
Comment
Number 5.3.2
Title Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
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
291
Comment
Number 5.3.2.1
Title Plasma Protein Binding Study Reports
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
292
Comment
Number
Title Study Report 1
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/study-report-1
293
Comment
Number
Title Study Report 2
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/study-report-2
294
Comment
Page 4-52
Number
Title Study Report 3
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/study-report-3
295
Comment
Number 5.3.2.2
Title Reports of Hepatic Metabolism and Drug Interaction Studies
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
296
Comment
Number
Title Study Report 1
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/study-report-1
297
Comment
Number
Title Study Report 2
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/study-report-2
298
Comment
Number
Title Study Report 3
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/study-report-3
299
Comment
Number 5.3.2.3
Title Reports of Studies Using Other Human Biomaterials
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
300
Comment
Number
Title Study Report 1
301
Element m5-3-2-3-reports-of-studies-using-other-human-biomaterials
Page 4-53
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-1
Comment
Number
Title Study Report 2
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/study-report-2
302
Comment
Number
Title Study Report 3
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/study-report-3
303
Comment
Number 5.3.3
Title Reports of Human Pharmacokinetic (PK) Studies
Element m5-3-3-reports-of-human-pharmacokinetics-pk-studies
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud
304
Comment
Number 5.3.3.1
Title Healthy Subject PK and Initial Tolerability Study Reports
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
305
Comment
Number
Title Study Report 1
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/study-report-1
306
Comment
Number
Title Study Report 2
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/study-report-2
307
Comment
308 Number
Page 4-54
Title Study Report 3
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/study-report-3
Comment
Number 5.3.3.2
Title Patient PK and Initial Tolerability Study Reports
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
309
Comment
Number
Title Study Report 1
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/study-report-1
310
Comment
Number
Title Study Report 2
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/study-report-2
311
Comment
Number
Title Study Report 3
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/study-report-3
312
Comment
Number 5.3.3.3
Title Intrinsic Factor PK Study Reports
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
313
Comment
Number
Title Study Report 1
Element m5-3-3-3-intrinsic-factor-pk-study-reports
314
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-1
Page 4-55
Comment
Number
Title Study Report 2
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-2
315
Comment
Number
Title Study Report 3
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-3
316
Comment
Number 5.3.3.4
Title Extrinsic Factor PK Study Reports
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
317
Comment
Number
Title Study Report 1
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/study-report-1
318
Comment
Number
Title Study Report 2
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/study-report-2
319
Comment
Number
Title Study Report 3
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/study-report-3
320
Comment
Number 5.3.3.5 321
Title Population PK Study Reports
Page 4-56
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
Title Study Report 1
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
322
Comment
Number
Title Study Report 2
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-2
323
Comment
Number
Title Study Report 3
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-3
324
Comment
Number 5.3.4
Title Reports of Human Pharmacodynamic (PD) Studies
Element m5-3-4-reports-of-human-pharmacodynamics-pd-studies
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud
325
Comment
Number 5.3.4.1
Title Healthy Subject PD and PK/PD Study Reports
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
326
Comment
Number
Title Study Report 1
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/study-report-1
327
Comment
Page 4-57
Number
Title Study Report 2
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/study-report-2
328
Comment
Number
Title Study Report 3
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/study-report-3
329
Comment
Number 5.3.4.2
Title Patient PD and PK/PD Study Reports
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
330
Comment
Number
Title Study Report 1
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/study-report-1
331
Comment
Number
Title Study Report 2
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/study-report-2
332
Comment
Number
Title Study Report 3
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/study-report-3
333
Comment
Number 5.3.5
Title Reports of Efficacy and Safety Studies
334
Element m5-3-5-reports-of-efficacy-and-safety-studies
Page 4-58
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
335
Comment
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'.
The ‘indication’ attribute in the backbone should be consistent with that used in the folder name but can be different. For example, an
‘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
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
336
Comment
Number
Title Study Report 1
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/study-report-1
337
Comment
Number
Title Study Report 2
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/study-report-2
338
Comment
Number
Title Study Report 3
Element m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
339
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-3
Page 4-59
Comment
Number 5.3.5.2
Title Study Reports of Uncontrolled Clinical Studies
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
340
Comment
Number
Title Study Report 1
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/study-report-1
341
Comment
Number
Title Study Report 2
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/study-report-2
342
Comment
Number
Title Study Report 3
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/study-report-3
343
Comment
Number 5.3.5.3
Title Reports of Analyses of Data from More than One Study
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
344
Comment
Number
Title Study Report 1
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/study-report-1
345
Comment
Number 346
Title Study Report 2
Page 4-60
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/study-report-2
Comment
Number
Title Study Report 3
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/study-report-3
347
Comment
Number 5.3.5.4
Title Other Study Reports
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
348
Comment
Number
Title Study Report 1
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/study-report-1
349
Comment
Number
Title Study Report 2
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/study-report-2
350
Comment
Number
Title Study Report 3
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/study-report-3
351
Comment
Number 5.3.6
Title Reports of Postmarketing Experience
Element m5-3-6-reports-of-postmarketing-experience
Directory m5/53-clin-stud-rep/536-postmark-exp
352
Comment
Page 4-61
Number 5.3.7
Title Case Report Forms and Individual Patient Listings
Element m5-3-7-case-report-forms-and-individual-patient-listings
Directory m5/53-clin-stud-rep/537-crf-ipl
353
Comment
Number
Title Study 1
Element m5-3-7-case-report-forms-and-individual-patient-listings
Directory m5/53-clin-stud-rep/537-crf-ipl/study-1
354
Comment
Number
Title Document/Dataset 1
Element m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-1.pdf
355
Comment
The filename and extension should include the description of the file and appropriate file extension according to Appendix 2. Reference
should be made to regional guidance for the acceptability of submission of datasets
Number
Title Document/Dataset 2
Element
m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-2.pdf
356
Comment
Number
Title Document/Dataset 3
Element m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-3.pdf
357
Comment
Number
Title Study 2
Element m5-3-7-case-report-forms-and-individual-patient-listings
Directory m5/53-clin-stud-rep/537-crf-ipl/study-2
358
Comment define element
Number 359
Title Document/Dataset 1
Page 4-62
Element m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-1.pdf
Comment
Number
Title Document/Dataset 2
Element m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-2.pdf
360
Comment
Number
Title Document/Dataset 3
Element m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-3.pdf
361
Comment
Number
Title Study 3
Element m5-3-7-case-report-forms-and-individual-patient-listings
Directory m5/53-clin-stud-rep/537-crf-ipl/study-3
362
Comment define element
Number
Title Document/Dataset 1
Element m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-1.pdf
363
Comment
Number
Title Document/Dataset 2
Element m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-2.pdf
364
Comment
Number
Title Document/Dataset 3
Element m5-3-7-case-report-forms-and-individual-patient-listings
File m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-3.pdf
365
Comment
Page 4-63
Number
5.4
Title Literature References
Element m5-4-literature-references
Directory m5/54-lit-ref
366
Comment Copies of literature references should ordinarily be submitted as individual files (i.e,. one for each reference).
Number
Title Reference 1
Element m5-4-literature-references
File m5/54-lit-ref/reference-1.pdf
367
Comment
Number
Title Reference 2
Element m5-4-literature-references
File m5/54-lit-ref/reference-2.pdf
368
Comment
Number
Title Reference 3
Element m5-4-literature-references
File m5/54-lit-ref/reference-3.pdf
369
Comment
Page 4-64
Number
Title
Element
Directory util
370
Comment utilities
Number
Title
Element
Directory util/dtd
371
Comment
DTDs/Schemas – it is not necessary to include regional DTDs/Schemas other than the one for the region to which the application is being
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
Element
File util/dtd/ich-ectd-n.dtd
372
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
Element
File util/dtd/eu-regional-n.dtd
373
Comment DTD for the EU specific documentation. “n” denotes the specific version (e.g., 1-1).
Number
Title
Element
File util/dtd/jp-regional-n.xsd
374
Comment Schema for the Japan specific documentation. “n” denotes the specific version (e.g., 1-0).
Number
Title
Element
File util/dtd/us-regional-n.dtd
375
Comment DTD for the US specific documentation. “n” denotes the specific version (e.g., 1-0).
Page 4-65
Number
Title
Element
File util/dtd/xx-regional-n.dtd
376
Comment
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.,
1-0).
Number
Title
Element
Directory util/style
377
Comment Directory for style sheets – ICH and regional stylesheets
Number
Title
Element
File util/style/ectd-n.xsl
378
Comment
The specific version of the eCTD stylesheet used by the applicant as a reference during the creation of the submission should be included.
“n” denotes the specific version (e.g., 1-0).
Number
Title
Element
File util/style/xx-regional-n.xsl
379
Comment
Stylesheet for the xx specific documentation, where xx is a two character country code from ISO-3166-1. “n” denotes the specific version
(e.g., 1-0).
Page 5-1
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].eu
Food And Drug Administration,
USA
www.fda.gov/cber
www.fda.gov/cder
Ministry of Health, Labour and
Welfare, Japan
http://www.mhlw.go.jp
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
or national agencies
http://www.emea.europa.eu
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
America
http://www.fda.gov/
Health Canada, Health Protection Branch, Canada http://www.hc-sc.gc.ca
Page 5-2
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 5-3
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 6-1
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 6-2
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
ctd-123456/0001 index.xml
index-md5.txt
ctd-123456/0001/m1/us us-regional.xml
ctd-123456/0001/util/dtd ich-ectd-3-x.dtd
us-regional-vx-x.dtd
ctd-123456/0002 index.xml
index-md5.txt
ctd-123456/0002/m1/us us-regional.xml
ctd-123456/0002/util/dtd ich-ectd-3-x.dtd
us-regional-vx-x.dtd
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 6-3
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
when using the Agency review
software
Operation
attribute
value Meaning
This leaf Previous leaf
New The leaf element has no relationship with leaf elements
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.
Current
Append This means there is an existing leaf element to which
this new leaf element should be associated. (e.g.,
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.
Current Current -
Appended
Replace This means there is an existing leaf element that this Current Replaced
Page 6-4
What the reviewer might see
when using the Agency review
software
Operation
attribute
value Meaning
This leaf Previous leaf
new leaf element replaces.
Delete There is no new file submitted in this case. Instead, the
leaf element has the operation of “delete” and the
“modified-file” attribute identifies the leaf element in a
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 (“”).
No longer
relevant to the
review
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
sequence #
File name Operation File Being
Modified
Sample logical display
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 6-5
Table 6-5
Submission
sequence #
File name Operation File Being Modified Sample logical display
in a review tool
0000 0000\…\structure.pdf New structure.pdf (current)
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
version of this file.
- 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
sequence #
File name Operation File Being Modified Sample logical display
in a review tool
0000 0000\…\structure.pdf New structure.pdf (current)
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
version of this file.
- 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
sequence #
File name Operation File Being
Modified
Sample logical display in
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 6-6
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 6-7
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