Guidance for Industry 

Granularity Document 

Annex to 

M4: Organization of the CTD 

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 

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 
TABLE OF CONTENTS 

INTRODUCTION......................................................................................................................... 1

ANNEX : GRANULARITY DOCUMENT................................................................................ 2

Definition of a Document.............................................................................................................. 2

Module 2..................................................................................................................................................3

Module 3..................................................................................................................................................4

Module 4..................................................................................................................................................6

Module 5..................................................................................................................................................7

Document Pagination and Segregation....................................................................................... 8

Section Numbering Within Documents ...................................................................................... 8

Table of Contents Formatting...................................................................................................... 8

Module 2..................................................................................................................................................8

Module 3..................................................................................................................................................9

Module 4..................................................................................................................................................9

Module 5................................................................................................................................................10
Contains Nonbinding Recommendations

1

Guidance for Industry1

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. 

INTRODUCTION 

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. 

 

1 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. 
Contains Nonbinding Recommendations

2

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? 

Definition of a Document

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. 
Contains Nonbinding Recommendations

3

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 

Introduction 

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 Note 2

2.3.S.7 

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 Note 3

2.3.P.8 

2.3.A.1 

2.3.A.2 

2.3.A 

2.3.A.3 

2.3 Note 1

2.3.R 

2.4 

2.5 

2.6.1 

2.6.2 

2.6.3 

2.6.4 

2.6.5 

2.6.6 

2.6 

2.6.7 

2.7.1 

2.7.2 

2.7.3 Note 4

2.7.4 

2.7.5 

Module 2 

2.7 

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. 
Contains Nonbinding Recommendations

4

Module 3 

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.S.1.1 

3.2.S.1.2 

3.2.S.1 

3.2.S.1.3 

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 

3.2.S.2.6 

3.2.S.3 3.2.S.3.1 

3.2.S.3.2 

3.2.S.4.1 

3.2.S.4.2 

3.2.S.4.3 

3.2.S.4.4 

3.2.S.4 

3.2.S.4.5 

3.2.S.5 

3.2.S.6 

3.2.S.7.1 

3.2.S.7.2 

3.2.S Note 2

3.2.S.7 

3.2.S.7.3 

3.2.P.1 

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 

3.2.P.2.6 

3.2.P.3.1 

3.2.P.3.2 

3.2.P.3.3 

3.2.P.3.4 

3.2.P.3 

3.2.P.3.5 

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 

3.2.P.4.6 

3.2.P.5.1 

3.2.P.5.2 

3.2.P.5.3 

Module 3 Note 1

3.2 

3.2.P Note 3

3.2.P.5 

3.2.P.5.4 
Contains Nonbinding Recommendations

5

3.2.P.5.5 

3.2.P.5.6 

3.2.P.6 

3.2.P.7 

3.2.P.8.1 

3.2.P.8.2 

3.2.P.8 

3.2.P.8.3 

3.2.A.1 

3.2.A.2 

3.2.A 

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. 
Contains Nonbinding Recommendations

6

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 

4.2.1.1 Studies Note 1

4.2.1.2 Studies Note 1

4.2.1.3 Studies Note 1

4.2.1 

4.2.1.4 Studies Note 1

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 

4.2.2.7 Studies Note 1

4.2.3.1 Studies Note 1

4.2.3.2 Studies Note 1

4.2.3.3.1 Studies Note 1 4.2.3.3 

4.2.3.3.2 Studies Note 1

4.2.3.4.1 Studies Note 1

4.2.3.4.2 Studies Note 1

4.2.3.4 

4.2.3.4.3 Studies Note 1

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 

4.2.3.5.4 Studies Note 1

4.2.3.6 Studies Note 1

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 

4.2.3 

4.2.3.7 

4.2.3.7.7 Studies Note 1

Module 4 

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. 
Contains Nonbinding Recommendations

7

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 

5.3.1.1 Studies Note 1

5.3.1.2 Studies Note 1

5.3.1.3 Studies Note 1

5.3.1 

5.3.1.4 Studies Note 1

5.3.2.1 Studies Note 1

5.3.2.2 Studies Note 1

5.3.2 

5.3.2.3 Studies Note 1

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 

5.3.3.5 Studies Note 1

5.3.4.1 Studies Note 1 5.3.4 

5.3.4.2 Studies Note 1

5.3.5.1 Studies Note 1

5.3.5.2 Studies Note 1

5.3.5.3 Studies Note 1

5.3.5 Note 2

5.3.5.4 Studies Note 1

5.3.6 

5.3 

5.3.7 Studies Note 1

Module 5 

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. 
Contains Nonbinding Recommendations

8

Document Pagination and Segregation 

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. 

Section Numbering Within Documents 

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. 

Table of Contents Formatting 

Module 2 

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.) 
Contains Nonbinding Recommendations

9

Module 3 

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. 

Module 4 

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. 
Contains Nonbinding Recommendations

10

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. 

Module 5 

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.