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.
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.
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.
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.)
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.
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.
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.
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: Applicant’s
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."
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.
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.