Guidance for Industry
Granularity Document
Annex to
M4: Organization of the CTD
(PDF
version of this document)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
October 2005
ICH
Additional copies are available
from:
Office of Training and
Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
Office of Communication, Training
and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
October 2005
ICH
Guidance for Industry
Granularity Document
Annex to M4: Organization of the CTD
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. You can use an alternative approach if that approach
satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach,
contact the FDA staff responsible for implementing this guidance.
If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.
This is one in a series of guidances that
provide recommendations for applicants preparing the Common
Technical Document for the Registration of Pharmaceuticals for Human
Use (CTD) for submission to the U.S. Food and Drug Administration
(FDA). This annex to the M4 guidance on the organization of the CTD
was developed by ICH in response to requests for additional
information after the harmonized CTD guidance documents were
finalized in November 2000. The annex is intended to clarify what
constitutes a document in the paper CTD and in the eCTD, and
includes the following information for modules 2 through 5:
-
location and hierararchy of headings within the
modules
-
document pagination and segregation
-
section numbering within documents
-
formatting of the table of contents
The information
provided here reflects the consensus of the ICH parties. The annex
will be incorporated in FDA’s next revision of the M4 guidance.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
ANNEX : Granularity Document
The CTD specifies many section headings and
numbers. Could guidance be provided for all modules on headings in
relation to document location and the section headings within those
documents? Could guidance also be provided on where in the CTD and
eCTD multiple documents can be located in the hierarchy?
Could guidance be given on how documents
should be paginated and on what the module Table of Contents should
therefore include?
A document is defined for a paper submission as
a set of pages, numbered sequentially and divided from other
documents by a tab (see Document Pagination and Segregation section
of this Annex). A document can be equated to a file for an
electronic submission. The granularity of the paper and electronic
submissions should be equivalent, although if a paper submission is
updated to be an electronic submission, some changes in granularity
could be introduced to facilitate on-going lifecycle management. In
an electronic submission, a new file starts at the same point at
which, in a paper submission, a tab divides the documents.
In deciding whether one or more documents or
files are appropriate, it should be considered that once a
particular approach has been adopted, the same approach should be
used throughout the life of the dossier since it is the intention
that replacement documents/files be provided when information is
changed.
The following tables describe the levels in the
CTD/eCTD hierarchy at which documents/files should be placed and
whether single or multiple documents are appropriate at each point.
This describes all sections of a CTD/eCTD, but for individual
submissions, all sections might not be applicable.
Module 2 |
2.1 |
The TOC is only called for in the paper version of the CTD;
there is no entry needed for the eCTD |
2.2 |
|
|
2.3
Note 1 |
Introduction |
|
2.3.S
Note 2 |
2.3.S.1 |
2.3.S.2 |
2.3.S.3 |
2.3.S.4 |
2.3.S.5 |
2.3.S.6 |
2.3.S.7 |
2.3.P
Note 3 |
2.3.P.1 |
2.3.P.2 |
2.3.P.3 |
2.3.P.4 |
2.3.P.5 |
2.3.P.6 |
2.3.P.7 |
2.3.P.8 |
2.3.A |
2.3.A.1 |
2.3.A.2 |
2.3.A.3 |
2.3.R |
|
2.4 |
|
|
2.5 |
|
|
2.6 |
2.6.1 |
|
2.6.2 |
|
2.6.3 |
|
2.6.4 |
|
2.6.5 |
|
2.6.6 |
|
2.6.7 |
|
2.7 |
2.7.1 |
|
2.7.2 |
|
2.7.3
Note 4 |
|
2.7.4 |
|
2.7.5 |
|
2.7.6 |
|
Key |
Documents rolled up to this level are not considered appropriate |
One document may be submitted at this level |
Note 1 : Optionality of granularity for the
Quality Overall Summary is provided in order to accommodate
different levels of complexity of products. The applicant can
choose the level at which the QOS is managed.
Note 2 : One document should be submitted for
each drug substance.
Note 3 : For a drug product supplied with
reconstitution diluent(s), the information on the diluent(s) should
be provided in a separate part “P” document.
Note 4 : One document for
each indication should be submitted, although closely related
indications can be within a single document.
Module 3
Note 1 |
3.1 |
The TOC is only called for in the paper version of the CTD;
there is no entry needed for the eCTD |
|
3.2 |
3.2.S
Note 2 |
3.2.S.1 |
3.2.S.1.1 |
|
3.2.S.1.2 |
|
3.2.S.1.3 |
|
3.2.S.2 |
3.2.S.2.1 |
|
3.2.S.2.2 |
|
3.2.S.2.3 |
|
3.2.S.2.4 |
|
3.2.S.2.5 |
|
3.2.S.2.6 |
|
3.2.S.3 |
3.2.S.3.1 |
|
3.2.S.3.2 |
|
3.2.S.4 |
3.2.S.4.1 |
|
3.2.S.4.2 |
|
3.2.S.4.3 |
|
3.2.S.4.4 |
|
3.2.S.4.5 |
|
3.2.S.5 |
|
|
3.2.S.6 |
|
|
3.2.S.7 |
3.2.S.7.1 |
|
3.2.S.7.2 |
|
3.2.S.7.3 |
|
3.2.P
Note 3 |
3.2.P.1 |
|
|
3.2.P.2 |
3.2.P.2.1
Note 4 |
|
|
3.2.P.2.2
Note 4 |
|
|
|
3.2.P.2.3 |
|
3.2.P.2.4 |
|
3.2.P.2.5 |
|
3.2.P.2.6 |
|
3.2.P.3 |
3.2.P.3.1 |
|
3.2.P.3.2 |
|
3.2.P.3.3 |
|
3.2.P.3.4 |
|
3.2.P.3.5 |
|
3.2.P.4 |
3.2.P.4.1 |
|
3.2.P.4.2 |
|
3.2.P.4.3 |
|
3.2.P.4.4 |
|
3.2.P.4.5 |
|
3.2.P.4.6 |
|
3.2.P.5 |
3.2.P.5.1 |
|
3.2.P.5.2 |
|
3.2.P.5.3 |
|
3.2.P.5.4 |
|
3.2.P.5.5 |
|
3.2.P.5.6 |
|
3.2.P.6 |
|
|
3.2.P.7 |
|
|
3.2.P.8 |
3.2.P.8.1 |
|
3.2.P.8.2 |
|
3.2.P.8.3 |
|
3.2.A |
3.2.A.1 |
|
|
3.2.A.2 |
|
|
3.2.A.3 |
|
|
3.2.R |
Note 5 |
|
|
3.3 |
One file
per reference Note 6 |
|
|
|
Key |
Documents rolled up to this level are not considered appropriate |
One or multiple documents can be submitted at this level |
Note 1 : In choosing the level of granularity
for this Module, the applicant should consider that, when relevant
information is changed at any point in the product's lifecycle,
replacements of complete documents/files should be provided
in the CTD and eCTD.
Note 2 : For a drug product containing more
than one drug substance, the information requested for part “S”
should be provided in its entirety for each drug substance.
Note 3 : For a drug product supplied with
reconstitution diluent(s), the information on the diluent(s) should
be provided in a separate part “P”, as appropriate.
Note 4 :
The lower level of headings included in CTD-Q at this point are
unlikely to be individual documents or files.
Note 5 : Refer to regional guidances.
Note 6 : Literature References should be listed
in the tables of contents.
Module 4 |
4.1 |
The TOC is only called for in the paper version of the CTD;
there is no entry needed for the eCTD |
4.2 |
4.2.1 |
4.2.1.1 |
Studies
Note 1 |
|
4.2.1.2 |
Studies
Note 1 |
|
4.2.1.3 |
Studies
Note 1 |
|
4.2.1.4 |
Studies
Note 1 |
|
4.2.2 |
4.2.2.1 |
Studies
Note 1 |
|
4.2.2.2 |
Studies
Note 1 |
|
4.2.2.3 |
Studies
Note 1 |
|
4.2.2.4 |
Studies
Note 1 |
|
4.2.2.5 |
Studies
Note 1 |
|
4.2.2.6 |
Studies
Note 1 |
|
4.2.2.7 |
Studies
Note 1 |
|
4.2.3 |
4.2.3.1 |
Studies
Note 1 |
|
4.2.3.2 |
Studies
Note 1 |
|
4.2.3.3 |
4.2.3.3.1 |
Studies
Note 1 |
4.2.3.3.2 |
Studies
Note 1 |
4.2.3.4 |
4.2.3.4.1 |
Studies
Note 1 |
4.2.3.4.2 |
Studies
Note 1 |
4.2.3.4.3 |
Studies
Note 1 |
4.2.3.5 |
4.2.3.5.1 |
Studies
Note 1 |
4.2.3.5.2 |
Studies
Note 1 |
4.2.3.5.3 |
Studies
Note 1 |
4.2.3.5.4 |
Studies
Note 1 |
4.2.3.6 |
Studies
Note 1 |
|
4.2.3.7 |
4.2.3.7.1 |
Studies
Note 1 |
4.2.3.7.2 |
Studies
Note 1 |
4.2.3.7.3 |
Studies
Note 1 |
4.2.3.7.4 |
Studies
Note 1 |
4.2.3.7.5 |
Studies
Note 1 |
4.2.3.7.6 |
Studies
Note 1 |
4.2.3.7.7 |
Studies
Note 1 |
4.3 |
One file per
reference
Note 2 |
|
|
|
Key |
Documents rolled up to this level are not considered appropriate |
One or multiple documents can be submitted at this level |
Note 1 : Typically, a single document should be
provided for each study report included 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
document. In this case, the text portion of the report should be
one document and the appendices can be one or more documents. 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 lifecycle, replacements of complete
documents/files should be provided.
Note 2 : Literature References should be listed
in the tables of contents.
Module 5 |
5.1 |
The TOC is only called for in the paper version of the CTD;
there is no entry needed for the eCTD |
5.2 |
|
|
|
5.3 |
5.3.1 |
5.3.1.1 |
Studies
Note 1 |
5.3.1.2 |
Studies
Note 1 |
5.3.1.3 |
Studies
Note 1 |
5.3.1.4 |
Studies
Note 1 |
5.3.2 |
5.3.2.1 |
Studies
Note 1 |
5.3.2.2 |
Studies
Note 1 |
5.3.2.3 |
Studies
Note 1 |
5.3.3 |
5.3.3.1 |
Studies
Note 1 |
5.3.3.2 |
Studies
Note 1 |
5.3.3.3 |
Studies
Note 1 |
5.3.3.4 |
Studies
Note 1 |
5.3.3.5 |
Studies
Note 1 |
5.3.4 |
5.3.4.1 |
Studies
Note 1 |
5.3.4.2 |
Studies
Note 1 |
5.3.5 Note 2 |
5.3.5.1 |
Studies
Note 1 |
5.3.5.2 |
Studies
Note 1 |
5.3.5.3 |
Studies
Note 1 |
5.3.5.4 |
Studies
Note 1 |
5.3.6 |
|
|
5.3.7 |
Studies
Note 1 |
|
5.4 |
One file per reference Note 3 |
|
|
Key |
Documents rolled up to this level are not considered appropriate
|
One document can be submitted at this level |
One or multiple documents can be submitted at this level |
Note 1 : The applicants should ordinarily
provide the study reports as multiple documents (a synopsis, a main
body of the study report 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 lifecycle, replacements of complete
documents/files should be provided.
Note 2 : For applications in support of more
than one indication, this section should be repeated for each
indication.
Note 3 : Literature References should be
listed in the tables of content.
Every document should be numbered starting at
page one, except for individual literature references, where the
existing journal page numbering is considered sufficient. Applicants
need not display the number as '1 of n' where n is the total number
of pages in the document.
Additionally, all pages of a document should
include a unique header or footer that briefly identifies its
subject matter. In a paper-based drug submission, a similar
identifier should be used on a tab that precedes the document, to
facilitate finding that document within the dossier. An abbreviation
of the full section number and title can be used.
If a section contains more than one document, a
specific Table of Contents for that section can be included to
identify the chronology and titles of the documents contained
therein, e.g.,
·
Tab with “3.2.S.4.2 Analytical Procedures”
o
Table of Contents, listing the title of Procedure A,
Procedure B, Procedure C
·
Tab with “3.2.S.4.2 “Procedure A”;
o
Procedure A (i.e. document, page
1-n)
·
Tab with “3.2.S.4.2 “Procedure B”;
o
Procedure B (i.e. document, page
1-n)
·
Tab with “3.2.S.4.2 “Procedure C”;
o
Procedure C (i.e. document, page
1-n)
If a section contains only a single document
(e.g. 3.2.S.1.1 Nomenclature), only a tab identified by “3.2.S.1.1
Nomenclature” should precede the document.
In order to avoid 5th, 6th,
etc., level subheading numbering (e.g., 2.6.6.3.2.1) within a
document, the applicant can use a shortened numbering string. In
this case, the document number and the name (e.g., 2.6.6 Toxicology
Written Summary) should appear in page headers or footers and then
section numbering within the document can be used, for example, 1,
1.1, 2, 3, 3.1, 3.2. Use of the full numbering string (e.g.,
2.6.6.3.2.1) is also considered acceptable.
The 2.1 CTD Table of Contents should go down to
the third (e.g., 2.3.S) or fourth (e.g., 2.3.S.1) level, depending
on how a document is defined for the Quality Overall Summary. (See
Definition of a document for Module 2.)
The Table of Contents provided under 3.1 should
cover the high-level section numbering, the associated section
heading and the Volume number in the order that they appear in the
drug submission. This Table of Contents would be used to identify
the contents of Module 3 as defined in the M4Q guideline. It should
go down to the fifth level only (e.g., 3.2.P.2.1). Note that
additional subsections and subheadings are defined in the M4Q
guideline beyond this level (e.g., under 3.2.P.2) and this
formatting should be used within the dossier, despite not being
included in the 3.1 Table of Contents. The lower level Table of
Contents described under Document Pagination and Segregation
should be excluded from the 3.1 Table of Contents.
At the applicant’s discretion, a Table of
Contents can also be included for a particular section that contains
multiple documents, in order to identify the chronology and the
document subject matter. If there is a desire to introduce
additional headers or subsection numbering beyond those which are
defined in the M4Q guideline, these should only be included within a
document and should be created neither as a separate document nor as
a new subsection. In this case, a specific Table of Contents for
that document can be included to identify the chronology and titles
of the subsections contained therein. These documents and
subsections should not appear in the 3.1 Table of Contents.
Furthermore, additional attachments or
appendices should not be incorporated into this formatting, except
as a document under a section where multiple documents might be
provided. In this case, a cross-reference should be made within the
relevant section to the attached or appended document. If there is
a desire to append or attach additional information to a section
that is comprised of only one document, this information should be
incorporated within that document.
All Table of Contents title entries should
either correspond to heading names and section numbering as defined
in the M4Q guideline or to identifiers appearing on tabs (for a
paper-based drug submission only), preferably by their full title,
which should easily identify any abbreviated title that might be
used on the corresponding tab. The Table of Contents should not
specify any page numbers.
Literature References should be listed in a
Table of Contents specific for this section.
The Table of Contents for Module 4 should
include all of the numerical items listed in the CTD guideline in
order to identify all of the important components of the application
(for example, 4.2.3.5.1 Fertility and early embryonic development)
and should continue down to at least the level of the study report.
Thus, each study report should be identified in the table of
contents. The sections of a study report could be identified in the
Module 4 Table of Contents of the dossier or only in the Table of
Contents of the individual study report.
Illustration of part
of the Module 4 Table of Contents
4.2.3.2
Repeat-Dose Toxicity
Study aa-aaa:
30 day repeat dose toxicity study with Drug C in rat
Study bb-bbb:
6 month repeat dose toxicity study with Drug C in rat
Study cc-ccc:
30 day repeat dose toxicity study with Drug C in dog
Study dd-ddd:
6 month repeat dose toxicity study with Drug C in dog
4.2.3.3
Genotoxicity
4.2.3.3.1 In vitro
Study ee-eee:
Ames test with Drug C
etc.
The Table of Contents for Module 5 should
include all of the numerical items listed in the CTD guideline in
order to identify all of the important components of the application
(for example, 5.3.5.1.1 Placebo Controlled Trials) and should
continue down to at least the level of the clinical study report.
Thus each clinical study report should be identified in the table of
contents. The sections of a clinical study report (E3) could be
identified in the Module 5 Table of Contents of the dossier or only
in the Table of Contents of the individual clinical study report.
Illustration of part
of the Module 5 Table of Contents
5.3.5 Indication Z - Reports of Efficacy and
Safety Studies
5.3.5.1 Indication Z - Study Reports of Controlled Clinical Trials
Pertinent to the Claimed Indication
5.3.5.1.1
Indication Z - Placebo Controlled Trials
Study xx-xxx: A double blind, placebo-controlled trial of
Drug A in Indication Z
Study yy-yyy:
A double blind……
5.3.5.1.2
Indication Z - Active Controlled Trials
Study zz-zzz: A double blind, active controlled trial of
Drug A vs. Drug C in Indication Z
5.3.5 Indication Q - Reports of Efficacy and
Safety Studies
5.3.5.1 Indication Q - Study Reports of
Controlled Clinical Trials Pertinent to the Claimed Indication
etc.
This guidance was developed
within the M4 CTD and M2 eCTD Implementation Working Groups of
the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH)
and has been subject to consultation by the regulatory parties,
in accordance with the ICH process. This document has been
endorsed by the ICH Steering Committee at Step 4 of the
ICH process in September 2002. A revision was signed off by ICH
in November 2003, and the annex was corrected in Janaury 2004.
At Step 4 of the process, the final draft is recommended
for adoption to the regulatory bodies of the European Union,
Japan, and the United States.
Back
to Top
Back to Guidance Page
Date created: |