Guidance for Industry 
  
M4:  The CTD  General   

Questions and Answers  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
 
December 2004  

ICH 
 
 
Revision 3  

  
 
 
   
Guidance for Industry 
 
 
M4:  The CTD  General  
 
Questions and Answers  

 
 
 
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 
 
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(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 
 
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http://www.fda.gov/cber/guidelines.htm. 
 
 (Tel) Voice Information System at 800-835-4709 or 301-827-1800 
 
 
 
 
 
 
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) 
 
 
December 2004
  
ICH 
  
 
Revision 3 

   
TABLE OF CONTENTS  
 
 
 
I.   INTRODUCTION .................................................................................................................1 
 
II.   BACKGROUND....................................................................................................................2 
 
III.   QUESTIONS AND ANSWERS............................................................................................2 
 
  Contains Nonbinding Recommendations  
1
 
Guidance for Industry  
M4: The CTD  General 
 
Questions and Answers  

 
 
 
 
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.  
 
 
 
I.   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 guidance provides answers 
to questions that have arisen since the finalization of the harmonized CTD guidance documents 
in November 2000.  This guidance addresses general questions about the CTD.  Other question 
and answer (Q & A) guidances are under development to address questions related specifically to 
quality, safety, and efficacy.  The questions and answers provided here reflect the consensus of 
the ICH parties.  
 
This guidance is being revised to include additional questions.  
  
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.  
 
                                                 
1  This guidance was developed within the M4 CTD Implementation Working Group 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, June 10, 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.  
 
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  Contains Nonbinding Recommendations  
II.   BACKGROUND 
 
 
The guidance for industry issued in November 2000 on preparing the CTD was divided into four 
separate documents:  (1) M4:  Organization of the CTD, (2) M4Q: The CTD  Quality, (3) 
M4E: The CTD  Efficacy, and (4) M4S: The CTD  Safety.  Since implementation of these 
guidances, a number of questions regarding the various CTD documents have been submitted to 
the various ICH regions.  The ICH has developed a process for responding to questions 
submitted to the ICH Web site.  
 
 
III.	   QUESTIONS AND ANSWERS  
 
Q1:  	 Format or Content?  
 
  Will a dossier using the CTD format (Modules 2 to 5) be identical for all regions?  
 
A1: 	  Not necessarily.  The CTD provides a common format for the submission of information 
to regulatory authorities in the three ICH regions.  However, the CTD does not address 
the content of submission. There are many regional requirements, as well as applicants 
preferences, that could affect the contents of dossiers submitted in each region.  
 
 
Q2:  	 Expert Reports  
 
  Are expert reports still required for submissions under the CTD format?  
 
A2: 	  No. Expert reports are replaced by Module 2. For specific European requirements 
regarding experts signatures, please refer to the European Commission Web Site.  
 
 
Q3:  	 Tables of Contents and Pagination  
 
For a paper CTD submission, the guidance states that for the comprehensive Table of 
Contents (TOC) in Module 1, no page numbers should be used. Does this apply only to 
the TOC in Module 1, or for all TOCs in every module? Also, besides the volume 
numbers and tab identifiers, should the module numbers also be included? For 
Modules 3, 4, and 5, should the volume number be part of the Table of Contents?  
 
A3: 	  There are no specific guidelines for the page numbers of the TOC.  Module numbers, 
volume numbers, and tab dividers should be part of all TOCs.  
 
 
 
 
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  Contains Nonbinding Recommendations  
Q4:  	 How to Paginate Literature References  
 
When provided, how should literature references be paginated in a paper CTD?  
Should each reference start with page 1, or should the page number from the source 
(journal, abstract, etc.) be the only page number included?  
 
A4: 	  Literature references should be paginated according to the page numbering of the source 
(journal, abstract, etc.).  
 
 
Q5:  	 Subheading numbering, or numbering within sections  
 
How should subnumbering within a document be organized? Some documents can be 
up to 50 pages in length with no defined CTD guidance heading and potentially, 
therefore, no TOC entries or bookmarks (in the electronic version).  Some guidance 
would be welcome to avoid regional interpretations on what is considered acceptable.  
 
A5: 	  Within the document, the applicant can use section numbers at a lower level than those 
specified in the CTD guidance.  However, there should be no other headings appearing in 
the overall TOC going below the numbering given in the CTD guidance.  
 
For example, for section 3.2.P.3.3, it would be possible to use subsequent numbers 
(3.2.P.3.3.1, 3.2.P.3.3.2, etc.) to provide further navigation within the document.  These 
should not appear in the overall TOC but can be included as bookmarks within the PDF 
files.  
 
 
Q6:  	 Titles of Documents Within Sections (e.g., Reports)  
 
In the header or footer of each document in a dossier, the appropriate TOC title entry 
should be included. In the case of, for example, a clinical report, the TOC entry is the 
title of the report and this can be very long. Would the use of the report number 
(alone) be considered sufficient? In other words, can the layout of the pages 
throughout the dossier be different: one page layout for reports and another one for 
Quality sections?  
 
A6: 	  It is recommended that a distinct identifier be put in headers/footers on every page. 
However, it does not need to be the full title.  An abbreviation would suffice.  
 
 
Q7:  	 Cross-References/Cross-Strings (in Paper Submissions)  
 
It is stated in the CTD that the section should be indicated in cross-strings.  What is 
meant here: The section number, or the section number and section name?  (In many 
cases, the section name is way too long to indicate in a cross-string.)  
 
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  Contains Nonbinding Recommendations  
A7: 	  (This answer was revised at the November 2003 ICH meeting.)  Providing the section 
header in addition to the section number improves the clarity of the reference, particularly 
for the uninitiated reader. To reduce the length of the cross string while maintaining the 
ease of use, it is recommended to include only the section number in the cross string and 
write the text so the reader will also know the section content. For example, ...as seen in 
the population PK study 101 (5.3.3.5) helps the reader to find the referenced study 
report under the Population PK Study Reports section. The text ...no safety problems 
were noted in the uncontrolled pneumonia study 101A (5.3.5.2) helps the reader find the 
referenced study report under the section Study Reports of Uncontrolled Clinical Studies 
for the Pneumonia indication.  
 
 
Q8:  	 General Glossary of Terms  
 
  Will there be a general glossary of recommended terminology for use in the CTD?  
 
A8:	   No glossary of terms is planned at this time.  
 
 
Q9:  	 Location of the information on Biological Comparability  
A combined comparability section might be beneficial to the review process. Is it 
possible to consider a modification to the CTD to provide for such a section for 
Biological products?  
 
Currently, comparability data should be included under 2.3.S32/3; preclinically as 
proposed; and clinically under 2.5.2 and 2.5.6. Each part should summarize briefly the 
conclusions from the other sections.  
 
   In the clinical summary, antigenicity should go under either 2.7.4.3 or 2.7.4.4.  
 	  In the clinical summary, AEs of special interest and Mortality and Hospital Re
admission should go under 2.7.4.2.1.4 (Other significant AEs).  
 
A9:	   No, for the moment the ICH does not foresee a separate CTD section combining all the 
comparability data.  
 
 
Q10:  	 Information for Generic Drug Applications  
 
Should the preclinical and clinical summary sections of the CTD be included in 
applications for generic drug approvals?  More specifically, are Modules 4 and 5 of the 
CTD applicable to abbreviated new drug applications (ANDAs) in the United States 
and Abridged Marketing Authorization applications in the European Union? Both 
categories of applications apply to generic drug applications, which ordinarily provide 
preclinical and clinical data based on available literature.  
 
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  Contains Nonbinding Recommendations  
A10: 	  The CTD provides a format for the submission of information to regulatory authorities. 
It does not define content.  Please refer to region-specific requirements to determine 
content requirements for the specific submission.  
 
 
Q11:  	 Font Style and Size  
 
On the basis of corporate identity we use the font style Arial for all of our documents. 
Can we use the font style Arial for CTDs, or do we have to use Times New Roman style 
to match the recommendation for narrative texts according to the guidance for 
industry M4: Organization of the CTD?  
 
A11: 	  Times New Roman 12 point is recommended for use in the CTD. This corresponds to MS 
Mincho, 10.5 point for the text written in Japanese.  
 
 
Q12:  	 Language   
 
Can the CTD be in any language (e.g., Japanese, German, French, English)? Is it 
limited to a single language?  
 
A12: 	  The CTD does not address this issue.  Please refer to regional guidance.  
 
 
Q13a:  Changes in Numbering and Section Headers  
 
With regard to the changes in numbering and section headers (September 11-12, 
2002), are the details in brackets (e.g., name, manufacturer or name, dosage form) 
only for use in eCTD format or for paper files also?  
 
A13a:   These changes apply to all CTD/eCTD submissions.  
 
 
Q13b:  Headers and Page Numbering  
 
What are your recommendations for externally produced documents (e.g., 
chromatograms, CTD format DMFs) regarding page numbering and appropriate 
headers? Are there allowances regarding these documents with regard to pagination 
and headers (i.e., are we allowed to submit them in the relevant document without a 
header or page number)?  
 
A13b:  Please refer to Q & A no. 5 above.  
 
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  Contains Nonbinding Recommendations  
Q13c:  Tabs  
 
Do tabs have to be printed? Do we have to use the full title with the number string on 
the tab? This is very difficult if the title is long.  
 
A13c:   Tabs should be printed for a paper submission.  Tab abbreviations are acceptable.  
 
 
Q14:  	 Is there a difference in the level of analysis in the nonclinical overview and the clinical 
overview in Module 2? Is there a difference between critical analysis (nonclinical 
overview) and critical assessment (clinical overview).  
 
A14: 	  Please refer to the general guidance for both the nonclinical and clinical overviews.  The 
level of analysis does not differ between these two overviews.  The guidance describes 
the information that should be included in the critical and integral assessment/analysis 
in both overviews.  
 
 
Q15:  	 Is the term section defined in the CTD?  Is there a different use of the term in Modules 
2 and 3? Do the ICH regions define sections differently?  
 
A15: 	  Each section in the CTD is identified by a number and a heading. Please refer to the 
Granularity Document Annex for a description documents to be provided in each section.  
The annex delineates when multiple documents per heading may be provided.  Also, refer 
to regional guidance as to when one or multiple documents should be provided per 
heading.  
 
 
Q16:  	 Does the deadline for mandatory submission of the CTD in Japan, the EU, and the 
United States (highly recommended in the United States) also refer to the eCTD?  
 
Has ICH considered planning a seminar to help with CTD and eCTD submissions?  
 
A16: 	  The deadline does not refer to the eCTD although the regulatory authorities are accepting 
eCTD submissions. Please refer to regional guidance for specific guidance on eCTD 
submissions.  
 
Currently the ICH is not planning to conduct a CTD seminar. However, the ICH6 

Conference, November 2003 in Osaka Japan, will focus on the CTD and eCTD.  

 
 
Q17:  	 Has the DTD reached its final stage of approval in the ICH process?  
 
A17: 	  The eCTD DTD has reached step 5 in the ICH process, which is the implementation step.  
 
 
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  Contains Nonbinding Recommendations  
Q18:   Is there a definition of which attachments should be included in the CTD?  
 
A18:   It is not suggested that additional attachments be included in the CTD.  
 
 
Q19:   CTD Training  
  
Does ICH recommend any particular comprehensive training course on the 
implementation of the CTD?  
 
A19:   No, there are no general ICH recommendations for training on CTD implementation.  
 
 
Q20:   Applicants Logo 
 
 Is it allowed to add the applicant's logo either on top of the CTD, or in the titles of 
CTD sections?  
 
A20:   The applicant is free to put his logo on top of the CTD.  However, logos are not 
acceptable in CTD sections' titles.  (The latter have been harmonized internationally; 
therefore applicants are not allowed to modify them.)  
 
 
Q21:   Herbal CTD  
 
Will a Herbal Products version of the CTD be published and how much will it vary 
from the pharmaceutical CTD?  
 
A21:   ICH does not plan to issue any specific version of the CTD for herbal products.  
 
 
Q22:   Granularity: Section Headings and Numbers, Documents Location/Hierarchy, 
Documents Pagination  
 
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?  
 
As a consequence of this definition could guidance be given on how documents should 
be paginated and on what the module Table of Contents should therefore include?  
 
A22:   Please refer to the Annex of the Organization of the Common Technical Document:  
"Granularity Document."  
 
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  Contains Nonbinding Recommendations  
Q23:   Is there a separate format for amendments and variations submitted in CTD format, or 
should applicants use the CTD format as it is now? If used as it is now, is it enough to 
simply indicate whatever modules are not used?  
 
A23:   The CTD structure is suitable for amendments and variations (refer to regional guidance 
for applicabilities).  The applicant should not submit the modules that are not used, i.e., it 
is unnecessary to include not applicable pages against unused CTD headings.  
 
 
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