Guidance for Industry

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)

August 2001

ICH
Guidance for Industry

M4: Organization of the CTD

Copies of this Guidance are available from:

Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

 5600 Fishers Lane, Rockville, MD 20857

(Phone 301-827-4573)

Internet: http://www.fda.gov/cder/guidance/index.htm.

or

 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

Internet: http://www.fda.gov/cber/guidelines.htm.

Fax: 1-888-CBERFAX or 301-827-3844

Mail: the 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)

August 2001

ICH
TABLE OF CONTENTS

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

BACKGROUND ........................................................................................................................... 2

The CTD .......................................................................................................................................2

Preparing and Organizing the CTD ..............................................................................................2

Organization and Format of the ICH Guidances for Industry ......................................................7

Numbering....................................................................................................................................7
1

Guidance for Industry1

M4: The Organization of the CTD

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 presents the agreed

upon common format for the preparation of a well-structured harmonized application that will be

submitted to regulatory authorities. A common format for the technical documentation will

significantly reduce the time and resources used to compile applications for registration of

human pharmaceuticals and will ease the preparation of electronic submissions. Regulatory

reviews and communication with the applicant will be facilitated by a standard document of

common elements. In addition, exchange of regulatory information among regulatory authorities

will be simplified.

Guidance for industry on preparing the CTD has been divided into four guidance documents on

(1) the organization of the CTD, (2) the quality section (3) the efficacy section (4) the safety

section. For specific information on the quality, efficacy, and/or safety sections of the CTD, see

the individual guidances for industry that discuss those parts of the CTD. For general

information about submitting a marketing application in the CTD format in the U.S. region, as

 

1 This guidance was developed by 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 was endorsed by the ICH Steering Committee at Step 4 of the

ICH process, November 2000. 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.

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. An alternative approach may be used if such approach satisfies the requirements of the

applicable statutes and regulations.
2

well as specific information about Module 1 (U.S. administrative information), see the guidance

for industry, General Considerations for Submitting Marketing Applications According to the

ICH/CTD Format.

2

 The CTD guidances are intended to be used together with other ICH and

Agency guidances. Please refer to those guidances for detailed information about the contents of

an application.

BACKGROUND

The CTD

Through the ICH process, considerable harmonization has been achieved among the three

regions (Japan, Europe, and the United States) in the technical requirements for the registration

of pharmaceuticals for human use. However, until now, there has been no harmonization of the

organization of a submission. Each region has its own requirements for the organization of the

technical reports in the submission and for the preparation of the summaries and tables. In

Japan, the applicants must prepare the GAIYO, which organizes and presents a summary of the

technical information. In Europe, expert reports and tabulated summaries are required, and

written summaries are recommended. The U.S. FDA has guidance regarding the format and

content of the new drug application submission. To avoid generating and compiling different

registration dossiers, this guidance describes a harmonized format for the CTD that will be

acceptable in all three regions.

Preparing and Organizing the CTD

This guidance addresses the general organization of the information to be presented in the CTD

application for new pharmaceuticals (including biotechnology-derived products). Guidance

documents also are available that discuss the Quality, Efficacy, and Safety sections of the CTD.

These guidances are not intended to indicate what studies are required. The guidances merely

indicate an appropriate format for the data that have been acquired. Applicants should not

modify the overall organization of the CTD. However, in the Nonclinical and Clinical

Summaries sections of the CTD, applicants can modify individual formats to provide the best

possible presentation of the technical information to facilitate the understanding and evaluation

of the results.

Throughout the CTD, the display of information should be unambiguous and transparent, to

facilitate the review of the basic data and to help a reviewer become quickly oriented to the

application contents. Text and tables should be prepared using margins that allow the document

to be printed on both A4 paper (E.U. and Japan) and 8.5 x 11” paper (U.S.). The left-hand

margin should be sufficiently large that information is not obscured through binding. Font sizes

for text and tables should be of a style and size that are large enough to be easily legible, even

after photocopying. Times New Roman, 12-point font is recommended for narrative text.

Acronyms and abbreviations should be defined the first time they are used in each module.

References should be cited in accordance with the current edition of the Uniform Requirements

 

2

 A draft version of the General Considerations guidance is currently available. Once it has been finalized, it will

represent the Agency's thinking on this topic.
3

for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal

Editors (ICMJE).3

The CTD should be organized into five modules. Module 1 is region specific. Modules 2, 3, 4,

and 5 are intended to be common for all regions. Conformance with the CTD guidances should

help ensure that these four modules are provided in a format acceptable to the regulatory

authorities (see the figure and overall outline on the following pages).

Module 1. Administrative Information and Prescribing Information

This module should contain documents specific to each region; for example, application

forms or the proposed label for use in the region. The content and format of this module

can be specified by the relevant regulatory authorities. For information about this module

see the guidance for industry, General Considerations for Submitting Marketing

Applications According to the ICH/CTD Format.

Module 2. Common Technical Document Summaries

Module 2 should begin with a general introduction to the pharmaceutical, including its

pharmacologic class, mode of action, and proposed clinical use. In general, the

introduction should not exceed one page.

Module 2 should contain 7 sections in the following order:

• CTD Table of Contents

• CTD Introduction

• Quality Overall Summary

• Nonclinical Overview

• Clinical Overview

• Nonclinical Written and Tabulated Summaries

• Clinical Summary.

Because Module 2 contains information from the Quality, Efficacy, and Safety sections

of the CTD, the organization of the individual Module 2 summaries is discussed in three

separate documents:

• M4Q: The CTD — Quality

• M4S: The CTD — Safety

• M4E: The CTD — Efficacy.

Module 3. Quality

Information on Quality should be presented in the structured format described in the

guidance, M4Q.

Module 4. Nonclinical Study Reports

 

3

 The first edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals was conceived

by the Vancouver Group and was published in 1979.
4

The Nonclinical Study Reports should be presented in the order described in the guidance

M4S.

Module 5. Clinical Study Reports

The human study reports and related information should be presented in the order

described in the guidance M4E .
5

Module 1

Regional

Administrative

Information

1

1.1 Submission

T of C

Quality

Overall

Summary

2.3

Nonclinical

Overview

2.4

Clinical

Overview

2.5

Nonclinical

Written and

Tabulated

Summaries

2.6

Clinical

Summary

2.7

Module 3

Quality

3

3.1 T of C

Module 4

Nonclinical

Study Reports

4

4.1 T of C

Module 5

Clinical

Study Reports

5

5.1 T of C

Module 2

Not Part of

the CTD

CTD

CTD Table of Contents

2.1

CTD Introduction

2.2

Diagrammatic Representation of the ICH Common Technical

Document
6

 The CTD should be organized according to the following general outline.

Module 1: Administrative Information and Prescribing Information

1.1 Table of Contents of the Submission Including Module 1

1.2 Documents Specific to Each Region (for example, application forms, prescribing

information)

Module 2: Common Technical Document Summaries

2.1 CTD Table of Contents

2.2 CTD Introduction

2.3 Quality Overall Summary

2.4 Nonclinical Overview

2.5 Clinical Overview

2.6 Nonclinical Written and Tabulated Summary

Pharmacology

Pharmacokinetics

Toxicology

2.7 Clinical Summary

Biopharmaceutics and Associated Analytical Methods

Clinical Pharmacology Studies

Clinical Efficacy

Clinical Safety

Synopses of Individual Studies

Module 3: Quality

3.1 Module 3 Table of Contents

3.2 Body of Data

3.3 Literature References

Module 4: Nonclinical Study Reports

4.1 Module 4 Table of Contents

4.2 Study Reports

4.3 Literature References

Module 5: Clinical Study Reports

5.1 Module 5 Table of Contents

5.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports

5.4 Literature References
7

Organization and Format of the ICH Guidances for Industry

The CTD is organized by modules. However, the guidances for industry that provide

recommendations for applicants on preparing the CTD have been organized by topic: Quality,

Safety, and Efficacy. The three guidances are organized as follows:

• Guidance on the Quality section of the CTD (Module 2, Quality Overall Summary

(QOS), and Module 3) can be found in the guidance for industry M4Q: The CTD —

Quality.

• Guidance on the Safety section of the CTD (Module 2, the Nonclinical Overview and the

Nonclinical Written and Tabulated Summaries, and Module 4) can be found in the

guidance for industry M4S: The CTD — Safety

• Guidance on the Efficacy section of the CTD (Module 2, the Clinical Overview and the

Clinical Summary, and Module 5) can be found in the guidance for industry M4E: The

CTD — Efficacy.

Because Module 2 contains information from Modules 3, 4, and 5, specific guidance on Module

2 is divided among the three guidances.

Numbering

In the guidances for industry on the Quality, Safety, and Efficacy sections of the CTD, Arabic

numbers have been assigned to designate those specific sections that should be included in the

CTD. The Arabic numbers used in the guidances also should be used when assembling the CTD

for submission. For specific information on numbering the pages and volumes of the

submission, see the guidance for industry General Considerations for Submitting Marketing

Applications According to the ICH/CTD Format. Sections in the guidance documents that are

not numbered provide guidance on how to prepare those sections.

It is possible that information for more than one drug substance, drug product, or indication will

be submitted. In such cases, please continue the use of Arabic numbers by repeating the specific

section’s numbering, making it clear that the data are for an additional drug substance, drug

product, or indication. For example, for an additional indication, repeat section 2.7.3, including

the name of the additional indication (e.g., 2.7.3 pneumonia, 2.7.3 URI). The same approach

should be used in the Quality section of the application for additional drug substances (2.3.S) and

drug products (2.3.P).