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eCTD Digital Handbook

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eCTD Digital Handbook


Table of Contents
Introduction by Emily Ethridge, Editor, FDAnews
Part 1 Tutorial
Section 1.0 eCTD Tutorial Table of Contents.
This FDA tutorial, consisting of seven PowerPoint presentations, provides an overview of
FDA's eCTD guidance document and a comprehensive discussion on preparing the five modules
of an eCTD. Emphasis is placed on ensuring the successful submission of an application and
facilitating the review process.
Section 1.1 eCTD Module 1.
This presentation provides information on:
o Archiving regional documents.
o Application management.
o Special regulatory programs.
o The legal and regulatory framework for the application/submission
Section 1.2 FDA Overview of the eCTD Guidance and its Implementation.
This presentation helps the student on:
o Electronic submission guidances using eCTD specifications providing regulatory submissions
in electronic format for human pharmaceutical product applications and related submissions.
Includes NDA, ANDA, BLA, IND, DMF and associated submissions.
o Preferred format for submissions
Section 1.3 Ensuring an Effective Submission.
This section discusses the top 10 eCTD issues for success:
1. PDF documents include TOCs.
2. PDF hyperlinks/bookmarks are correct.
3. XML must be standard components.
4. Documents conform to eCTD granularity.
5. MD5 checksum are correct.
6. Unneeded node extensions are removed.
7. Sequence numbers are 4 digit.
8. Application numbers are 6 digits.
9. eCTD submissions include Module 1.
10. Files referenced in the XML backbone(s).
Section 1.4 Guidance Compliant eCTDs Module 4.
This section discusses Module 4 and the positions of its various components.
Section 1.5 Guidance-Compliant eCTDs- Module 5.

Section 1.5 discusses the purpose and structure of Module 5:


o Provides framework for clinical documents submitted during drug development (IND); e.g.
protocols, protocol amendments, IND safety reports.

o
o
o
o
o

One section contains all information to perform in-depth clinical pharmacology and clinical/
statistical BLA/NDA review.
Permits comprehensive clinical pharmacology, clinical, statistical reviews.
Majority of IND/BLA/NDA clinical content in section 5.3.
A study report now comes in multiple files (E3) *different from the past.
Datasets and CRFs organized by study, but still XPT and PDF, respectively.

Section 1.6 eCTDs Quality CMC Issues.


This section outlines and describes the following issues:
o Historical FDA e-submission efforts.
o How to read the eCTD DTDs.
o Repeated sections.
o Location issues in Module 3.
o Topics appearing in multiple sections.
o Issues to be resolved.
Section 1.7 Prequel Template or Guidance.
This presentation provides advice on:
o Background/Motivation.
o ICH CTDGeneral guidance on summariesAnnex: granularity document.
o Module 2: Summaries.
o Mapping from the CFR .
o Module 4: Safety.
Part 2 Guidances
Section 02 Guidance for Industry M4 The CTD - Efficacy Questions and Answers.
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. This guidance specifically addresses questions related to efficacy. Other question
and answer (Q &A) guidances are under development to address general questions as well as
questions related to quality and safety. The questions and answers provided here reflect the
consensus of the ICH parties.
Section 03 Structure and Content of Clinical Study Reports.
The objective of this guideline is to facilitate the compilation of a single core clinical study
report acceptable to all regulatory authorities of the ICH regions. The regulatory authorityspecific additions will consist of modules to be considered as appendices, available upon request
according to regional regulatory requirements.
Part 3 Submissions
Section 04 Electronic Submission Guidances.
PowerPoint presentation on providing regulatory submissions in electronic format including:
o Overview.
o Available guidances-traditional electronic submissions.
o Electronic submissions using eCTD specifications.
o eCTD guidance changes from eNDA guidancecontinuation of eNDA guidance.
o Submissions 101 references.

Section 05 Providing Regulatory Submissions in Electronic Format Using eCTD Specifications.


This is one in a series of guidance documents intended to assist applicants making regulatory
submissions to the FDA in electronic format using the electronic common technical document
(eCTD) specifications. This guidance discusses issues related to the electronic submission of
applications for human pharmaceutical products and related submissions, including abbreviated
new drug applications (ANDAs), biologics license applications (BLAs), investigational new
drug applications (INDs), new drug application (NDAs), master files (e.g., drug master files),
advertising material, and promotional labeling. At this time, this does not include applications
supporting combination products.
Part 4 Technical Requirements.
Part 4 contains a number of specification, standards, definitions, presentations and checklists for creating
and maintaining an eCTD protocol within your company.
Section 6 Comprehensive eCTD Table of Contents Headings and Hierarchy.
This section includes the complete structure and numbering for content headings and the hierarchy
of Modules 1-5
Section 7 Conformance Review Checklist For NDAs.
This document provides a checklist for
o General issues.
o Organization of folders.
o Organization of the electronic submission.
Section 8 eCTD Backbone Files Specification for Module 1.
This document provides specifications for creating the electronic common technical document
(eCTD) backbone file for Module 1 for use with the guidance to industry: Providing Regulatory
Submissions in Electronic Format Human Pharmaceutical Applications and Related
Submissions.
Section 9 eCTD Backbone Files Specification for Modules 2 through 5.
This document provides specifications for creating the electronic common technical document
(eCTD) backbone file for modules 2 to 5 of the common technical document (CTD) for use
with the guidance to industry: Providing Regulatory Submissions in Electronic Format - Human
Pharmaceutical Applications and Related Submissions.
Section 10 eCTD Backbone Files Study Tagging Files.
In order to help identify all of the files associated with a study, information is needed on each
document including the document title, subject matter (defined by the headings under which the
documents are located in the table of contents), relationship to other documents, revision
information, the location of the document and information on the submission that included the
document. This document outlines the eCTD backbone files which include many of these
information items. However, the eCTD backbone files do not contain enough information on the
subject matter of several documents (e.g., study report documents) to support certain regulatory
business rules. This additional information is provided in the STF. The complete structure and
contents of the STF files is presented in this section.
Section 11 eCTD Change Control Process v1.8.
This document establishes the change control process for the eCTD Specification. Change
control for regional eCTD Module 1 specifications is the regional authority's responsibility.

Section 12 eCTD Change Request Form.


This form should be used to request a change to the ICH eCTD Specification. The change can
be to fix a perceived bug, meet a new requirement or to enhance existing functionality.
Section 13 eCTD Specification v 3.2.
This document describes the parts of the registration application that are common to all regions
and some of the lifecycle requirements for products. The parts of the registration application
that are specific to a region will be covered by regional guidance. However, this backbone has
been developed to handle both the regional and common parts of submissions.
Section 14 eSUBS and eCTDs: Practical Advice and Pitfalls to Avoid.
PowerPoint presentation outlining the factors to be aware of when submitting an eDoc:
o Correct use of elements and leaf titles.
o Always Reference all Files in the XML Backbone(s).
o Include Module 1 in all eCTD Submissions.
o Make Sure All Application Numbers are 6 Digits.
o Make Sure all Sequence Numbers are 4 Digits.
o Do Not Use Node Extension.
o Verify That All MD5 Checksums are Correct.
o All Documents Should Conform to eCTD Granularity.
o All XML must use standard components.
o Be Sure All PDF Hyperlinks & Bookmarks are Correct
o Include TOCs In All PDF Documents.
Section 15 Evaluation and Research ISS/ISE: Where Do They Fit in the CTD-eCTD.
PowerPoint presentation that provides advice on how to:
o Differentiate between ICH guidelines and FDA requirements for the CTD/eCTD.
o Identify the goals of the CTD/eCTD for both industry and regulators.
o Identify strategies to include the ISS/ISE in the CTD and eCTD submission formats.
Section 16 Future of Case Report Tabulation Submissions.
PowerPoint presentation on case report tabulations including discussion of:
o Study data standards.
o Status of patient profile pilot.
o Medical review technology for an NDA safety database.
Section 17 Granularity Document Annex M4 Organization of the CTD.
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.
Section 18 ICH eCTD Specification Document DTD 3.2.
This section includes code for the XML submission that needs to be created and validated
according to the XML eCTD DTD standard.
Section 19 Module 1 Document Type Definition File.
The ICH eCTD specification calls for a regional Module 1 document type definition file to
allow regional information to be submitted along with information from ICH Modules 2 to 5.
The section provided sample code for the FDA draft eCTD Module 1 DTD version 2.01 hierarchy.

Section 20 Placement of Integrated Summaries of Safety and Effectiveness (ISS/ISE) in


Applications Submitted in the eCTD Format.
The tables in this document are examples of the various sections of the CTD that contain sum
mary and integrated discussions of efficacy and safety and the corresponding FDA regulations,
where applicable, that inform the content of those sections.
Section 21 Portable Document Format Specifications.
These specifications are for submitting documents in Portable Document Format (PDF).
Section 22 Specification for Transmitting Electronic Submissions using eCTD Specifications.
This document provides specification for transmitting electronic submissions using eCTD
specifications. Details are included for transmitting the electronic submission on physical media
or electronically.
Section 23 Standards and Successful Document Creation.
PowerPoint presentation on standards issues including:
o ISS/ISE placement one of the most frequently asked questions.
o ISS/ISE Represent Analysis5.3.5.3 Reports of analyses of data from more than one
studyModule 5 provides necessary organization structures through STF.
o Module 2 SummariesCritical and Concise SummariesPage counts do not define whats
acceptable.
Section 24 Study Tagging File Workshop.
PowerPoint presentation that deals with 2 tagging file problems:
o The maximum of only 256 characters that can be used.
This is further limited by ICH to 230 characters to permit the ICH regulatory agencies space for
server and folders names to organize the submission.
ICH guidance recommends that folder names not exceed 64 characters.
o Computer Displays that cannot readily display lengthy path and filenames.
In many cases some filenames could be the same up to the ending making it difficult for reviewers.
Section 25 Transformation of the Backbone from XML to HTML.
eCTD the final ICH Step 4 eCTD specifications and draft specifications from the FDA to enable
the assembly of submission-ready documents, create the appropriate file/folder structure, assign
leaf document attributes, and then build the required XML backbone and regional XML
required in eCTD submissions.
Part 5 Training
Section 26 NDA Electronic Data Analysis Training.
CDER has provided guidance to industry for sponsors to send case report form tabulations and
individual animal line listings as datasets. To help Center review staff use these electronic
datasets, the Office of Information Technology, in conjunction with review staff, has developed
NDA Electronic Data Analysis Training (NEDAT).
Section 27 NDA Electronic Submissions Training.
In keeping with CDER's Electronic Regulatory Submission and Review (ERSR) goals, electronic
submissions are currently being placed on the CDER network for access and review by CDER
review staff. Currently, NDAs and their corresponding Amendments and Supplements are the
only submissions received in electronic format. Before these submissions can be reviewed, CDER
review staff must first be able to access an electronic submission folder on the network save a drive
path (map), copy the folders and files pertinent to their discipline, and learn to use the features
available in Adobe Acrobat. Reviewer staff then can access these electronic files from their desktop.

Introduction
By Emily Ethridge, Editor, FDAnews
The FDA is looking towards moving to an all-electronic submissions system for
regulatory information in all of its divisions to facilitate easier reviews and information
sharing. All submitted documents, such as new drug applications and marketing
materials, will come in electronic common technical document (eCTD) form.
Having data in a common electronic environment will allow the FDA to regulate
products quickly, eliminating difficulties with accessing, searching through and finding
data in paper forms.
The agency ultimately wants to create an electronic information exchange network to
share with the public, so that information can be traded between the FDA, investigators,
healthcare professionals, patients and other agencies.
Different product areas are in different stages of electronic submission requirements, and
changes will come in stages to each area. That is why it is essential for companies to
learn the details and standards for each type of electronic submission. Already the Center
for Drug Evaluation and Research has set a deadline for all submissions to arrive in
eCTD form.
While electronic submissions help the agency speed reviews and share information, they
also help companies. Using the eCTD costs less for companies than paper submissions,
freeing up resources that allow drugmakers to focus on interpreting clinical data instead
of handling that data.
Electronic submissions can be particularly helpful for companies considering a clinical
trial for a new indication of an approved drug, because it makes subsequent
communication with the FDA easier, more efficient and faster. Electronic submissions
create information collection mechanisms that make it easier for investigators to access
and interpret new data.
In this book, you will learn the benefits of switching to eCTD and the best practices for
the new format, as well as the specifications, standards and checklists for creating an
eCTD protocol in your company.
When the FDA held a public meeting on electronic submissions in December 2006,
several speakers noted challenges in switching to an electronic system, such as a current
lack of trained labor and standardized procedures. This book will help you navigate the
many FDA-issued documents to find the most valuable information so your company an
make a smooth transition to electronic submissions.
The book begins with a tutorial of seven PowerPoint presentations giving an overview of
the FDAs eCTD guidance document and how it will be implemented. The presentations

also provide a comprehensive discussion on preparing each of the five modules of an


eCTD.
Next, there are two industry guidances. The first focuses on efficacy questions in
preparing eCTD for the registration of pharmaceuticals in human use. The answers reflect
a consensus from the members of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals in Human Use (ICH).
Another guidance provides recommendations on compiling a single core clinical study
report acceptable to all regulatory authorities in ICH regions including Europe, Japan and
the United States.
To help with submissions, the book provides a presentation on providing regulatory
submission in electronic format. It also includes a guidance discussing issues related to
the electronic submission of applications, including abbreviated new drug applications,
biologics license applications, investigational new drug applications and new drug
applications,
The FDA suggests it is most beneficial to begin eCTD-based submissions with an initial
submission of an application and then following up with the appropriate center before
making eCTD-based submissions of other applications. This guidance covers each
pharmaceutical submission type, except for applications for combination products. The
guidance also suggests how to electronically submit master files, advertising materials
and promotional labeling.
The next part of the book, Section Four, covers specifications, standards, definitions and
checklists for creating and maintaining and eCTD protocol in the company. One
document provides specifications for creating eCTD backbone files for all five modules
in connection with industry guidances, as well as how to manage electronic study tagging
files.
Backbone files come in extensible markup language (XML) to replace the usual portable
document format (PDF) table of contents, because XML has more power to display data
and information, creating greater efficiency for the files. The book discusses how to
transform the backbone from XML to HTML. Without eCTD backbone files, the agency
will not be able to adequately manage or review submissions.
The eCTD backbone files include items such as the document title, subject matter,
relationships to other documents, revision information, the documents location and
submission information included in the document. However, the eCTD backbone files do
not have enough information on the subject matter of certain documents, such as study
report documents, to support some regulatory business rules. That information is
provided in backbone study tagging files.

A PowerPoint presentation explains how to deal with two common study tagging file
problems using a maximum of 256 characters and computer displays that cannot
display lengthy path and file names.
Another presentation in this section provides practical advice and pitfalls to avoid for
submitting an electronic document, including referencing all files in the XML backbones
and using standard XML components.
Another PowerPoint presentation explains how to differentiate between ICH guidelines
and FDA requirements, how to identify goals and strategies for both industry and
regulators.
This section also includes a sample form for requesting a change to the ICH eCTD
specification, which can be used to fix a bug or to meet new requirements. In addition,
there is a document describing the parts of the registration application common to all
regions and some of the lifestyle requirements for products, and another establishing the
change control process for the eCTD specification.
The section also provides the specifications for submitting documents in PDF and for
transmitting electronic submissions using eCTD specifications either electronically or on
physical media. It also contains a document detailing where to place the integrated
summaries of safety and effectiveness in applications submitted in eCTD format.
Part Five of the book deals with training and preparing your company for switching to
submissions in eCTD form. The first part covers new drug application electronic data
analysis training, created by the FDAs Office of Information Technology along with
review staff. The training covers a guidance from the Center for Drug Evaluation and
Research (CDER) for sponsors to send case report form tabulations and individual animal
line listings as data sets.
The second part provides step-by-step instructions on how to review submissions in
electronic format. Currently at CDER, only new drug applications and their
corresponding amendments and supplements are received in electronic formats. Before
staff can review the submissions, the employees must first be able to access an electronic
submission folder on the network, save a drive path, copy the pertinent files and folders
and learn to use the features available in Adobe Acrobat.
Although the FDA may not be prepared to make a full switch to electronic document
formats right away, it is clearly trying to forge a path ahead to reach its ultimate goal of
all-electronic submissions. The agency has detailed its specifications, checklists,
definitions and objectives. With these tools and other industry documents, your company
can keep up with every detail and request in the process of switching to electronic
document formats.

Part 1
Tutorial

SECTION 1.0

This FDA tutorial, consisting of seven PowerPoint presentations, provides an


overview of FDA's eCTD guidance document and a comprehensive discussion on
preparing the five modules of an eCTD. Emphasis is placed on ensuring the successful submission of an application and facilitating the review process.

Electronic Common Technical Document (eCTD) Tutorial

This tutorial will provide an overview of FDA's eCTD guidance document and a comprehensive
discussion on preparing the five modules of an eCTD. Emphasis will be placed on ensuring the
successful submission of an application and facilitating the review process.
1.
2.
3.
4.
5.
6.
7.

eCTD: Module 1, Bronwyn Collier, FDA


eCTD Guidance Overview, Gary M. Gensinger, MBA, FDA
Ensuring a Effective Submission, Gary M. Gensinger, MBA, FDA
Guidance Compliant eCTDs Module 4: Safety, Steve Wilson, DrPH, CAPT USPHS, FDA
Guidance-Compliant eCTDs: Module 5, Armando Oliva, M.D., FDA
eCTDs Quality/CMC Issues, Norman R. Schmuff, Ph.D., FDA
Prequel 1: Template or Guidance? Steve Wilson, DrPH, CAPT USPHS, FDA

SECTION 1.1

eCTD Module 1

This presentation provides information on:


o Archiving regional documents
o Application management
o Special regulatory programs
o The legal and regulatory framework for the application/submission

eCTD: Module 1
Bronwyn Collier, Associate Director for Regulatory Affairs
Office of Drug Evalaution III
Center for Drug Evaluation and Research
FDA

April 2005

Module 1: Topics
Purpose
Impact on review process
Module 1 table of contents

Module 1: Purpose
Archive regional documents
Application management
Status
Business
Special regulatory programs
Provides the legal and regulatory framework
for the application/submission

Impact on Review Process


Facilitates document processing
Identification
Division assignment

Review assignment
Guides response
Satisfies some regulatory requirements

TOC Mapping
CFR Citation

eCTD/STF Heading

NUMBER

TITLE

312.7(d)

Charging for and


commercialization
of investigational
drugs

1.12.2

Request to
Charge

312.10

Waivers

1.12.5

Request for a
waiver

312.23
(a)(1)

Cover sheet (Form


FDA 1571)

1.1.1

Application
form: FDA form
1571

N/A

N/A

N/A

1.3.5.1

312.23(a)(2) Table of Contents


314.50(h)

Patent Information

MODULE NUMBER

TITLE

Patent
Information
5

Module 1 TOC
1.1 Forms
1.1.1 Application form: FDA form 1571
1.1.2 Application form: FDA form 356(h)
1.1.3 User fee cover sheet: FDA form 3397
1.1.4 Annual report transmittal: FDA form
2252
1.1.5 Advertisements and promotional
labeling transmittal: FDA form 2253
1.1.6 Transmittal of labels & circulars: FDA
form 2567
6

Module 1 TOC
1.2 Cover letters
Submission identification
Submission description
Approximate submission size
Virus free statement
Regulatory & technical point of contact

Module 1 TOC
1.3 Administrative information
1.3.1 Contact/sponsor/applicant information

1.3.1.1 Change of address or corporate name


1.3.1.2 Change in contact/agent
1.3.1.3 Change in sponsor
1.3.1.4 Transfer of obligation
1.3.1.5 Change in ownership of an application

1.3.2 Field copy certification


1.3.3 Debarment certification
1.3.4 Financial certification and disclosure
8

Module 1 TOC
1.3.5 Patent and exclusivity
1.3.5.1 Patent information
FDA form 3542a
FDA form 3542

1.3.5.2 Patent Certifications


1.3.5.3 Exclusivity request

1.4 References
1.4.1 Letter of authorization
1.4.2 Statement of right of reference
1.4.3 List of authorized persons to incorporate by
reference
1.4.4 Cross reference to other applications and
previously submitted information

Module 1 TOC
1.5 Application status

1.5.1 IND Withdrawal request


1.5.2 Inactivation request
1.5.3 Reactivation request
1.5.4 Reinstatement request
1.5.5 Withdrawal of an unapproved application
1.5.6 Withdrawal of listed drug
1.5.7 Request for withdrawal of application approval
1.5.8 Other correspondence re withdrawal or
suspension of approval
10

Module 1 TOC
1.6 Meetings
1.6.1 Meeting request
1.6.2 Meeting background materials
1.6.3 Correspondence regarding meetings

1.7 Fast track


1.7.1 Fast track designation request
1.7.2 Fast track designation withdrawal
request
1.7.3 Rolling review request
Correspondence re Fast Track/Rolling Review
Correspondence re CMA Pilot 1
Correspondence re CMA Pilot 2
11

Module 1 TOC
1.8 Special protocol assessment request
1.8.1 Clinical study
1.8.2 Carcinogenicity study
1.8.3 Stability study

12

Module 1 TOC
1.9 pediatric administrative information
1.9.1 Request for deferral
1.9.2 Request for waiver
1.9.3 Request for pediatric exclusivity
determination
1.9.4 Proposed pediatric study request and
amendments
1.9.5 Proposal for written agreement
1.9.6 Other correspondence regarding
pediatric exclusivity or study plans
13

Module 1 TOC
1.10 Dispute resolution
1.10.1 Request for dispute resolution
1.10.2 Correspondence related to dispute
resolution

1.11 Information amendment (info not


covered under modules 2-5
1.11.1 Quality information amendment
1.11.2 Safety information amendment
1.11.3 Efficacy information amendment
14

Module 1 TOC
1.12 Other correspondence

1.12.1 Pre IND correspondence


1.12.2 Request to charge
1.12.3 Notification of charging under treatment IND
1.12.4 Request for comments and advice on an IND
1.12.5 Request for a waiver
1.12.6 Exemption from informed consent for
emergency research
1.12.7 Public disclosure statement for emergency
care research
1.12.8 Correspondence regarding emergency care
research
15

Module 1 TOC

1.12.9 Notification of discontinuation of clinical trial


1.12.10 Generic drug enforcement act statement
1.12.11 Basis for submission statement
1.12.13 Comparison of generic drug and reference
listed drug
1.12.14 Request for waiver for in vivo studies
1.12.15 Environmental assessment
1.12.16 Request for waiver of in vivo bioavailability
studies
1.12.17 Field alert reports
16

Module 1 TOC
1.13 Annual report
1.13.1 Summary for nonclinical studies
1.13.2 Summary of clinical pharmacology
information
1.13.3 Summary of safety information
1.13.4 Summary of labeling changes
1.13.5 Summary of manufacturing changes
1.13.6 Summary of microbiological changes
17

Module 1 TOC

1.13.7 Summary of other significant new information


1.13.8 Individual study information
1.13.9 General Investigational plan
1.13.10 Foreign marketing history
1.13.11 Distribution data
1.13.12 Status of postmarketing study commitments
1.13.13 Status of other postmarketing studies
1.13.14 Log of outstanding regulatory business

18

Module 1 TOC
1.14 labeling
1.14.1 Draft labeling

1.14.1.1 Draft carton and container labels


1.14.1.2 Annotated draft labeling text
1.14.1.3 Draft labeling text
1.14.1.4 Label comprehension studies
1.14.1.5 Labeling history

19

Module 1 TOC
1.14.2 Final labeling
1.14.2.1 Final carton and container labels
1.14.2.2 Final package insert (package inserts,
patient information, Medication guides)
1.14.2.3 Final labeling text

1.14.3 Listed Drug labeling


1.14.3.1 Annotated comparison with listed drug
1.14.3.2 Approved labeling text for listed drug
1.14.3.3 Labeling text for reference listed drug

20

Module 1 TOC
1.14.4 Investigational drug labeling
1.14.1.1 Investigators brochure
1.14.1.2 Investigational drug Labeling

1.14.5 Foreign labeling


1.15 Promotional material
1.16 Risk management plans

21

Summary
Module 1 sets the regulatory and legal
framework for applications and
subsequent submissions
Match information to appropriate heading

22

SECTION 1.2

FDA Overview of the eCTD


Guidance and its Implementation

This presentation provides assistance on:


o Electronic submission guidances using eCTD specifications providing
regulatory submissions in electronic format for human pharmaceutical
product applications and related submissions.
Includes NDA, ANDA, BLA, IND, DMF and associated submissions.
o Preferred format for submissions.

eCTD Guidance Overview

Gary M Gensinger, MBA


Director, Review Technology Staff
Center for Drug Evaluation and Research

esub@cder.fda.gov

Overview
Available Guidances
Traditional Electronic Submissions
Electronic Submissions using eCTD
Specifications

eCTD Guidance
Changes from eNDA Guidance
Continuation of eNDA Guidance

Submissions 101 References


esub@cder.fda.gov

Electronic Submission Guidances


Traditional Electronic Submission

Providing Regulatory Submissions in


Electronic Format
NDA (Published January, 1999)
Advertising and Promotional Labeling
(Published January 2001)
ANDA (Published June, 2002)
Periodic Safety Report (Published June
2003)
esub@cder.fda.gov

Electronic Submission Guidances


Using eCTD Specifications

Providing Regulatory Submissions in


Electronic Format - Human Pharmaceutical
Product Applications and Related
Submissions
All submission types
NDA, ANDA, BLA, IND, DMF, Annual Reports, Periodic
Safety Reports, Advertising and Promotional Labeling

Published as draft August 28, 2003


Preferred Format for Submissions

esub@cder.fda.gov

Electronic Submissions Using eCTD


Specifications
Guidance Published August, 2003
eCTD Specifications
FDA eCTD Table of Contents Headings and Hierarchy
FDA Module 1 Specification
FDA Modules 2 to 5 Specification
Study Tagging File Specification

Specifications Available On-Line


http://www.fda.gov/cder/regulatory/ersr/default.htm

Current eNDA/eANDA Guidances remain available


as an alternative to the eCTD

esub@cder.fda.gov

eCTD Changes

XML-based eCTD Backbone replaces PDF Tables of Content


Increased document granularity in accordance with ICH eCTD
agreements
No requirement to submit technical sections or study reports in
paper
EVS processor performs rigid validation of backbone against
DTD
Requires strict adherence to specifications
Do not add or modify leafs within the backbone
Once a submission is sent in eCTD format all future
submissions for the application should be in eCTD format
Opportunity to use Part 11 Compliant Electronic Signatures

esub@cder.fda.gov

What doesnt change


Data files submitted in SAS XPORT
format
Documents submitted in PDF Format
Draft labeling submitted in MS Word
Office XP is being deployed

esub@cder.fda.gov

Implementing the Guidance


Initial Pilot Phase
Contact CDER prior to generating pilot submission
Review process and make adjustments

Pilot submission evaluated for technical


compliance only unless directed otherwise
Accepting all submission types, e.g., IND,
NDA, Amendments, Master Files, Annual
Reports

esub@cder.fda.gov

Submissions 101

esub@cder.fda.gov

Just say no
No paper unless required for original
signatures
No Word files or file formats not
specified in the guidance
No electronic submissions or records
sent directly to a reviewer or project
manager
No electronic desk copies
esub@cder.fda.gov

Just dont do it
Dont send electronic submissions to
the division document rooms
Dont use node extensions in preparing
eCTD
Dont combine multiple documents into
single PDF
Dont send customized style sheets
Dont hide your media place it in the
volume with your cover letter.
esub@cder.fda.gov

References
CDER Contact for information on eCTD
submissions
eSub@cder.fda.gov

Electronic Regulatory Submissions and


Review website
http://www.fda.gov/cder/regulatory/ersr/default.htm

International Conference on Harmonization


http://www.ich.org

esub@cder.fda.gov

SECTION 1.3

Ensuring an Effective Submission

This section discusses the top 10 eCTD issues for success:


1. PDF documents include TOCs.
2. PDF hyperlinks/bookmarks are correct.
3. XML must be standard components.
4. Documents conform to eCTD granularity.
5. MD5 checksum are correct.
6. Unneeded node extensions are removed.
7. Sequence numbers are 4 digit.
8. Application numbers are 6 digits.
9. eCTD submissions include Module 1.
10. Files referenced in the XML backbone(s).

Ensuring a Effective Submission

Gary M Gensinger, MBA


Director, Review Technology Staff
Center for Drug Evaluation and Research

esub@cder.fda.gov

Remember!
One of your goals is communication
Clarity improves reviewability
Consider application from reviewers
standpoint
Create document level Tables of Content
with appropriate bookmarks
Use meaningful file names
Use clear concise leaf titles
esub@cder.fda.gov

Have a Pre-Meeting to Discuss the


Electronic Submission
Schedule prior to assembling
application, e.g., 6 to 12 months prior to
submission of NDA
Discuss data, datasets, format

esub@cder.fda.gov

Contact Electronic Submission


Coordinator
Initiate contact prior to assembling
application
Arrange participation in eCTD Pilot
Clarify Guidance questions
Contact addresses:
esub@cder.fda.gov

esub@cder.fda.gov

Submitting Electronic Submissions


CDER: ODEI - ODEV
ALL electronic submissions for original applications,
supplements, and amendments, must be sent to the Central
Document Room

CDER: ODEVI
All electronic submission to the ODEVI document room

CDER: OGD
All electronic submission to the OGD document room

Send only ONE copy of the electronic submission


Use the correct electronic media and choose type
appropriate to size of submission
Place the electronic media in the first volume
esub@cder.fda.gov

Submitting Electronic Submissions


Continued

eCTD
Should not include any paper
If Part 11 compliant electronic signatures are available
otherwise only documents requiring original signatures

Include all required eCTD files


Include all required forms, letters, and
certifications
Be sure ALL files submitted are referenced in XML
backbone
Do not use Node extensions
esub@cder.fda.gov

Top 10 eCTD Issues for Success


10.
9.
8.
7.
6.
5.
4.
3.
2.
1.

Files Referenced in the XML Backbone(s)


eCTD Submissions Include Module 1
Application Numbers are 6 Digits
Sequence Numbers are 4 Digits
Unneeded Node Extensions are Removed
MD5 Checksum are Correct
Documents Conform to eCTD Granularity
XML must be Standard Components
PDF Hyperlinks/Bookmarks are Correct
PDF Documents include TOCs
esub@cder.fda.gov

10. All Files Referenced in the XML


Backbone(s)
Unreferenced Files Result from
Missing/Mislocated Directory references in
xlink:href
Extra files
Failing to Repeat Complete Directory Structure on
each media component in a set

Unreferenced Files cannot be located by


reviewers
Are complex directories structures really
needed ?
esub@cder.fda.gov

9. All eCTD Submissions Include


Module 1
Each and Every eCTD Requires Module 1
Module 1 Identifies important information

Company Name
Drug Name
Submission Type
Submission Date
Application Number
Sequence Number

esub@cder.fda.gov

8. All Application Numbers are 6 Digits


Application-number values must be 6 digits

No Alpha Characters
No - , or other punctuation
No spaces
Six Numbers pad left 0 if 5 digits are given

Application number is key - ties all


submissions together as an application

esub@cder.fda.gov

7. All Sequence Numbers are 4 Digits


Sequence-number values must be 4 digits
No Alpha Characters
No - , or other punctuation
No spaces

Sequence number is key and relates all


submission components together
Sequence numbers need not be
received/submitted in sequence

esub@cder.fda.gov

6. All Unneeded Node Extensions are


Removed
Node Extensions are Unwanted

ICH and FDA do not recommend NEs


At best they are ignored; at worst they defeat
the standard headings

Node Extensions are Unneeded

Leaf Title can be used to differentiate


between documents at the same level

esub@cder.fda.gov

5. All MD5 Checksums are Correct


MD5 Checksum values should be
Lower case
Coded as a leaf attribute in either us-regional.xml
or index.xml

Except
The MD5 Checksum value is provided in a one line
text file index-md5.txt in the 0000 (sequence
number directory).

esub@cder.fda.gov

4. All Documents Conform to eCTD


Granularity
Avoid combining documents at higher parent
leaf level (allowed by Module 3)

Tempting - small initial savings in combining


Large cost in life cycle complexity
Legacy Study Reports make for life cycle
issues down the road

esub@cder.fda.gov

3. All XML must be Standard


Components
UTIL Folder
3 Standard DTDs

3 Standard Styles Sheets in UTIL folder


Custom components create issues in FDA
Processes Defeat standards efforts

Avoid GIFs, custom CSS, custom DTDs,


custom elements with standard DTDs

esub@cder.fda.gov

2. All PDF HyperLinks & Bookmarks


are Correct
Validate all Hyperlinks and Bookmarks
Incorrect Targets Unnerve Reviewers
Reviewer Thinks: What else is wrong with
the submission?

esub@cder.fda.gov

1. All PDF Documents Include TOCs


For each Document If a paper document needs a TOC, a PDF
document needs a hyperlinked TOC
No change from eNDA - both bookmarks and
hyperlinks
Cross Document Links still work in an eCTD
All 4 RTFs to date have had errors in
bookmarks and TOC hyperlinks

esub@cder.fda.gov

Provide Bookmarks
with Intuitive Names
Good

Bad

esub@cder.fda.gov

Bookmarks
Useful to have a bookmarks back to
higher levels of the submission

esub@cder.fda.gov

Book Mark Issue Example

esub@cder.fda.gov

Ensuring a Effective Submission

Take advantage of FDAs help before


submitting your first eCTD
Review the Top 10 Issues
Validate that your submission is
complete on its face

esub@cder.fda.gov

References
CDER Contact for information on eCTD
and CTD submissions eSub@cder.fda.gov
Electronic Regulatory Submissions and
Review website
www.fda.gov/cder/regulatory/ersr/default.htm
International Conference on
Harmonization www.ich.org

esub@cder.fda.gov

SECTION 1.4

Guidance Compliant eCTDs


Module 4

This section discusses Module 4 and the positions of its various components.

Guidance Compliant eCTDs


Module 4: Safety
Steve Wilson, DrPH, CAPT USPHS
Deputy Director, Division of Biometrics II, CDER/FDA

ICH Public Meeting


April 22, 2005
Doubletree Hotel and Executive Business Center
1750 Rockville Pike, Rockville, MD

Disclaimer
Views expressed in this presentation
are those of the speaker and not,
necessarily, of the Food and Drug
Administration

Outline
Module 4 -- Safety
Continuing Education -Questions and Answers(?)
Final Exam

CTD Introduction: Safety

Module 4
Nonclinical
Study Reports
4
4.1 T of C

Module 4: Safety
4.2 Study reports
4.2.1 Pharmacology
4.2.2 Pharmacokinetics
4.2.3 Toxicology
4.3 Literature references

4.2.1 Pharmacology
4.2.1.1 Primary pharmacodynamics
4.2.1.2 Secondary pharmacodynamics
4.2.1.3 Safety pharmacology
4.2.1.4 Pharmacodynamic drug interactions

4.2.1.1 Primary Pharmacodynamics


Study report [identification number] and related
information
Legacy study report
Synopsis
Study report body
Protocol and amendments
Signatures of principal or coordinating
investigator(s)
Audit certifications and reports

4.2.1.1 Primary Pharmacodynamics


Documentation of statistical methods and interim
analysis plans
Documentation of inter laboratory standardization
methods of quality assurance procedures if used
Publications based on the study
Important publications referenced in the report
Compliance and/or drug concentration data
Individual subject data listings

4.2.1.1 Primary Pharmacodynamics


Data tabulation
Data tabulation datasets
Data definitions

Data listing datasets


Data listing datasets
Data definitions

Analysis datasets
Analysis datasets
Analysis programs
Data definitions

IND safety reports

4.2.1.2 Secondary Pharmacodynamics


Study report [identification number] and
related information
See Primary pharmacodynamics Study report
and related information for headings

Folder Structure of Module 4

Granularity: Module 4 -- Safety

4.2 Study Reports


4.2.1 Pharmacology
4.2.2 Pharmacokinetics
4.2.3 Toxicology
4.3 Literature references

Continuing Education
Questions & Answers (?)

Questions & Answers (?) CTD


M4: The CTD General Questions and Answers (October
2003)
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).
provides answers to questions that have arisen since the
finalization of the harmonized CTD guidance documents in
November 2000.
addresses general questions about the CTD.
Other question and answer ( Q & A) guidances quality, safety,
and efficacy.
The questions and answers provided here reflect the consensus of
the ICH parties.

Questions & Answers (?)


CTD/Safety

Continuing Education
www.fda.gov

The Latest News


sort by date

Questions & Answers (?) CTDs & eCTDs

Your Final Exam

Q10 Integrated Summary of Safety and


Effectiveness
Does the CTD section on safety in Module
2 replace the section under 21 CFR 314.50(
d)( 5)( v)-( vi) calling for integrated
summary of safety and effectiveness ( ISS/
ISE)?

Questions & Answers (?) CTDs & eCTDs

Your Final Exam Answer

A10: The ISS/ ISE are critical components of the


safety and effectiveness submission and are
expected to be submitted in the application in
accordance with the regulation.
FDAs guidance Format and Content of Clinical
and Statistical Sections of Application gives advice
on how to construct these summaries.
Note that, despite the name, these are integrated
analyses of all relevant data, not summaries.

Questions & Answers (?) CTDs & eCTDs

Your Final Exam Answer

The Clinical Safety sections of the CTD follow


approximately the outline of the sections of the
ISS/ ISE, although they are somewhat modified
by experience with ICH E-3 ( Structure and
Content of Clinical Study Reports).
The CTD Clinical Overview and Summary in
Module 2 will not usually contain the level of
detail expected for an ISS.
It may contain the level of detail needed for an
ISE, but this would need to be determined on a
case- by- case basis.

Questions & Answers (?) CTDs & eCTDs

Your Final Exam Answer

If the requirements of 21 CFR 314.50 can be met


for a particular application by what is in the
CTD Module 2 summary, the CTD Module 2
section would fulfill the need for an ISS/ ISE.
In some cases, it will be convenient to write
much of what is needed in the CTD Module 2
with appropriate appendices in Module 5.
In other cases, the ISS/ ISE would be
summarized in Module 2, with detailed reports
in Module 5.
Any questions about these matters can be raised
with the reviewing division.

Questions & Answers (?) CTDs & eCTDs

Your Final Exam

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
What about eCTDs?

Specifications

Efficient Drug Development

Watch This Space:ICH Terminology


Standards -- Proposed M6
Maintenance process for ICH Terminology
Lists
Objective
Develop maintenance process to keep
terminology lists in ICH guidances

Status
Concept paper accepted by steering
committee
Standard operating procedures being
developed
Pilot in 2005

Proposed M6 Maintenance Process


Collect change requests
Evaluate change requests
Decision process
Maintain terminology lists and codes
ICH web site
NCI Enterprise Vocabulary Services

THANK YOU
(301) 827-5583
wilsons@cder.fda.gov

SECTION 1.5

Guidance Compliant eCTDs


Module 5

Section 1.5 discusses the purpose and structure of Module 5:


o Provides framework for clinical documents submitted during drug development
(IND); e.g. protocols, protocol amendments, IND safety reports.
o One section contains all information to perform in-depth clinical pharmacology
and clinical/statistical BLA/NDA review.
o Permits comprehensive clinical pharmacology, clinical, statistical reviews.
o Majority of IND/BLA/NDA clinical content in section 5.3.
o A study report now comes in multiple files (E3) different from the past.
o Datasets and CRFs organized by study, but still XPT and PDF, respectively.

Guidance-Compliant eCTDs:
Module 5

Armando Oliva, M.D.


Associate Director for Policy
Company
logo here

Office of New Drugs


CDER / FDA
esub@cder.fda.gov

Overview
Organization of Module 5 What Goes
Where?
Study Reports
Data

esub@cder.fda.gov

Why Module 5?
Advantage for the Reviewer
Provides Framework for clinical
documents submitted during drug
development (IND); e.g. protocols,
protocol amendments, IND safety
reports
One section contains all information to
perform in-depth clinical pharmacology
and clinical/statistical BLA/NDA review
esub@cder.fda.gov

Advantage to Reviewer: Examples

NDA Amendments
Protocol Amendments (IND)

esub@cder.fda.gov

Organization
5.1 Table of Contents (in XML backbone)
5.2 - Tabular Listing of All Clinical Studies
5.3 Clinical Study Reports and Related
Information
5.4 Literature References
esub@cder.fda.gov

5.2 Tabular Listing of All Clinical Studies

A Single PDF File


No additional guidance at this time

esub@cder.fda.gov

Study No.

Title

Treatment

Duration

Treated

Location

PK
Studies
AA-001

[Title]

Placebo
1 mg
5 mg
10 mg

1 dose

10
10
10
10

5.3.3.1

AA-002

[Title2]

Placebo
1 mg q d
5 mg q d

2 weeks

10
20
20

5.3.3.1

[Title 3]

Placebo
5 mg qd

1 week

10
15

5.3.4.2

PD
Studies
AB-001

esub@cder.fda.gov

5.3 Clinical Study Reports


and Related Information
Biopharmaceutic, Pharmacokinetic,
Pharmacodynamic Studies (5.3.1, 5.3.2,
5.3.3, 5.3.4)
Safety and Efficacy Studies (Indication)
(5.3.5)

esub@cder.fda.gov

5.3.1

5.3.2

5.3.3

Biopharmaceutics

Human Biomaterials

Human PK Studies

Bioavailability (BA)

Plasma Protein Binding

Bioequivalence (BE)

Hepatic Metabolism

Healthy Subject /
Patient PK

In-vitro/in-vivo
correlation

Drug Interaction

Intrinsic Factor PK

In-vitro/in-vivo
correlation studies

Extrinsic Factor PK

Bioanalytical/Analytical
Methods for Human
Studies

Bioanalytical/Analytical
Methods for Human
Studies

5.3.4
Human PD
Healthy Subject PD and PK/PD
esub@cder.fda.gov

Population PK

5.3.5

5.3.6

Efficacy and Safety Studies


(Indication)

Postmarketing Experience

Controlled studies pertinent to claim

Postmarketing periodic adverse


event drug experience report

Uncontrolled studies

(not AERS reports)

Analyses of more than one study


Integrated Summary of Safety
Integrated Summary of Efficacy
Safety Updates
Other Study Reports
Antibacterial/antiviral/special
pathogens/immune modulator
esub@cder.fda.gov

All of these go in 5.3


New Protocols (IND) including Treatment
Protocols
Protocol Amendments
New Investigators; Investigators
Qualifications
IND Safety Report
Compliance with Informed Consent
Integrated Summaries of Efficacy and Safety
Postmarketing Periodic Adverse Drug
Experience Reports
esub@cder.fda.gov

Also in 5.3
Case Report Tabulations
Case Report Forms
Use appropriate sections under the specific
study

esub@cder.fda.gov

5.4 Literature References


Each reference is a single PDF file
Filenames should be short and
meaningful

esub@cder.fda.gov

Study Reports
Headings are Organized according to ICH
E3 document and report is submitted in
multiple files (*different from previous
guidance*)
Legacy Study Reports (ie, generated
before eCTD) one PDF file per report
(other than case report forms and
individual data listings)
esub@cder.fda.gov

Study Reports
One PDF file each for: (E3 reference)
Synopsis (2)
Study Report (3 to 15)
Appendices (16)
Protocol and amendments (16.1.1)
Sample Case Report Forms (16.1.2)
List of IECs IRBs (16.1.3) and consent forms
List/Description of Investigators/Sites (16.1.4)
Signatures of Principal Investigator(16.1.5)
List/Patients receiving Test Drug/batch (16.1.6)
esub@cder.fda.gov

Randomisation Scheme (16.1.7)


Audit certificates (16.1.8) and reports
Statistical Methods (16.1.9)
Inter-laboratory standardization method (16.1.10)
Publications based on the study (16.1.11)
References (16.1.12)
Discontinued Patients (16.2.1)
Protocol Deviations (16.2.2)
Patients excluded from efficacy studies (16.2.3)
Demographic Data (16.2.4)
Compliance/drug concentration data (16.2.5)
Individual Efficacy Response data (16.2.6)
Adverse Event listings (16.2.7)
Listing of individual laboratory measurement (16.2.8)
esub@cder.fda.gov

Case Report Forms (16.3)


Individual patient data listings (16.4)
Data tabulations
Data listings
Analysis datasets
Annotated case report forms
Subject profiles
IND safety reports

esub@cder.fda.gov

Study Tagging File (STF)


Allows study report headings/table of
contents to appear in eCTD table of
contents
Ease of navigation for the reviewer
XML file in the same folder as the
corresponding study files

esub@cder.fda.gov

Case Report Forms


One PDF file per subject
Unique subject identifier as title and
filename
Bookmark domains and study visits
For addenda and corrections: hypertext
link from amended item to the corrected
page
esub@cder.fda.gov

Study Data
File Formats:
SAS Transport (Version 5)
Organization
Datasets go in same section in the TOC
as its corresponding study report

esub@cder.fda.gov

Study Data: Folder Structure

esub@cder.fda.gov

FAQ
Q: ISE/ISS: Module 2 or Module 5?
A: Usually Module 5 (section 5.3.5.3) but
can be Module 2 if short. Discuss with
review division.
[remember Module 2 = 50-400 pages]

esub@cder.fda.gov

Summary
Module 5 permits comprehensive
clinical pharmacology, clinical, statistical
reviews
Majority of IND/BLA/NDA clinical
content in section 5.3
A study report now comes in multiple
files (E3) *different from the past*
Datasets and CRFs organized by
study, but still XPT and PDF,
respectively.
esub@cder.fda.gov

SECTION 1.6

eCTDs Quality CMC Issues


Module 5

This section outlines and describes the following issues:


o Historical FDA e-submission efforts.
o How to read the eCTD DTDs.
o Repeated sections.
o Location issues in Module 3.
o Topics appearing in multiple sections.
o Issues to be resolved.

eCTDs
Quality/CMC Issues
Norman R. Schmuff, Ph.D.
FDA, CDER
Acting Deputy Division Director
Division of New Drug Chemistry 3

ICH CTD Step-4 Group


San Diego, Nov 2000

ICH eCTD Step-4 Group


Tysons Corner, Sept 2002

Early FDA SGML-Based Initiatives


Publication: SGML for Regulatory Submissions
Early 1990s?, DIA Journal?, RAPS Journal?

FDA Presentations
June 1992
CANDA Conference
Aster Publishing
New Brunswick, NJ

July 1992
CANDA Conference
IIR
Princeton, NJ

Early SGML-Based Projects


DTD for CMC submission

Shown October 1993


GCA (Graphic Communication Assn) Meeting
Philadelphia, PA
Viewing of instance on Unix, Macintosh, and PC

Simultaneous activities at HPB, PharmaSoft


MERS (Multiagency Electronic Reg Submission)
January 31, 1994
Meeting at FDA w/ HPB (Bob Kapitany),
PharmaSoft (Per Manell)

A Little XML: Reading a DTD


XML
Extensible Markup Language
Unlike HTML, not a fixed tag set
start tag
end tag
<your-new-tag>
< /your-new-tag>
Two major components
DTD or Schema Heading names, Sequence,
Optionality, Repeatability, like an outline
Document Instance DTD/Scheme with data, like an
outline populated with data

There is a parent element (heading) called memo

<memo>

XML Memo Example

<date> 22 May 2004 </date>


memo is comprised of child elements,
<to id=123> Bill Monroe </to>
cc which
may
appear
zero must
or more
times
date,
to, from,
which
appear
and
<from id=345> Maybelle Carter
</from>
sub-topic
may appear
zero or
just once
(i.e. optional
but
canorder
repeat
indefinitely),
but
if it
must
be
in
the
given,
followed
by
(i.e.
optional,
but
cannot
repeat
)
<cc>
Bob Wills
</cc>
appears
at all, ID
it must
after the from
the
element
to has
a required
attribute
(ID isbe
a directly
special XML
body
must
appear
at
least
once
and
<topic> Picnic
</topic>
attribute
required
to be element
unique throughout an XML document, in this
can be repeated
case
it is an employees
identification
number)
<lead-para>
Our annual picnic
is scheduled..
</lead-para>
<body> Some details follow... </body>

<!ELEMENT memo (date, to, from, cc*, topic,


sub-topic?, lead-para, body+)>
<!ELEMENT date (#PCDATA)>
<!ELEMENT to (#PCDATA)>
<!ATTLIST to ID #REQUIRED>

DTD

</memo>

XML Memo
<!ELEMENT memo (date, to, from, cc*, topic, sub-topic?, lead-para, body+)>
<!ELEMENT date (#PCDATA)
<!ELEMENT to (#PCDATA)
<!ATTLIST to ID #REQUIRED>

MEMO
Date:
To:
From:
[CC:]
Topic:
[Sub-topic:]
Lead paragraph
Body
Body

+
*
?

one or more
zero or more
zero or one

eCTD Required Elements


<!-- ================== ADMIN ==================================== -->
<!ELEMENT admin (applicant-info, product-description, application-information)>
<!-- ********************* Applicant Information ******************** -->
<!ELEMENT applicant-info (company-name, date-of-submission)>
<!ELEMENT company-name (#PCDATA)>
<!ELEMENT date-of-submission (date)>
<!ELEMENT date (#PCDATA)>
<!ATTLIST date
format (yyyymmdd) #REQUIRED
>
<!-- ********************* Product Description ********************** -->
<!ELEMENT product-description (application-number, prod-name+)>
<!ELEMENT application-number (#PCDATA)>
<!ELEMENT prod-name (#PCDATA)>
<!ATTLIST prod-name
type (established | proprietary | chemical | code) #REQUIRED

eCTD Required Elements


From FDAs Module 1 DTD
<!-- ================== ADMIN ==================================== -->
<!ELEMENT admin (applicant-info, product-description, application-information)>
<!-- ********************* Applicant Information ******************** -->
<!ELEMENT applicant-info (company-name, date-of-submission)>
<!ELEMENT company-name (#PCDATA)>
<!ELEMENT date-of-submission (date)>Note: the absence of * or ? means all
<date format="yyyymmdd">20020208</date>
<!ELEMENT date (#PCDATA)>
of these elements are required, (i.e.
(tells
us
in the attributestart
what
date
format youre
with
<!-<!ATTLIST date
nonecomments
are optional), not
surprising
since
using,
since
a
DTD,
unlike
a
Schema,
cannot
format (yyyymmdd) #REQUIRED
otherwise administrative information
require
a specific data format)
>
might be incomplete
<!-- *********************
Product Description ********************** -->
<prod-name type=established">amoxicillin</prod-name>
<!ELEMENT product-description
(application-number,
prod-name+)>
(tells us that what
follows is the established
name)
<!ELEMENT application-number (#PCDATA)>
<!ELEMENT prod-name (#PCDATA)>
<!ATTLIST prod-name
type (established | proprietary | chemical | code) #REQUIRED

eCTD Optional Elements


(from P.8 Drug Product Stability)
<!ELEMENT m3-2-p-8-stability
((leaf)* ,
m3-2-p-8-1-stability-summary-and-conclusion? ,
m3-2-p-8-2-post-approval-stability-protocol-andstability-commitment? ,
m3-2-p-8-3-stability-data?)>
?

Optional element appears once or not at all


Optional and repeatable element may appear 0 or more
times

Example Content Model


(from P.8 Drug Product Stability)
< !ELEMENT m3-2-p-8-1-stability-summaryand-conclusion
((leaf | node-extension)*)>

Optional element appears once or not at all


Optional and repeatable element may appear 0 or more
times

Quality/CMC Information
Module 1 (Region Specific Information)
Environmental Assessment

Module 2 (Summaries)
2.3 Quality Overall Summary
(Note: only one summary, unlike E & S sections)

Module 3

Drug Substance
Drug Product
Appendices
Regional Information

Submitting to Multiple Applications


Identical information may apply to multiple
applications (i.e. NDAs, ANDAs, BLAs)
Examples:
Amendment to original NDAs for different
dosage forms
CMC supplement w/ API change for all approved
dosage forms

Submitting to Multiple Applications


Current Module 1 DTD does not allow a
single submission to apply to multiple
applications
Workaround
Submit the data once, along with the backbone for
NDA #1
Then, submit only the backbone for NDA #2, etc.
E.g., for applications AP1, AP2, AP3 which have CMC data in common, submit
the file in AP1 sequence 0004 where the leaf would have:
xlink:href="m3/32bodydata/32p-drug-prod/xxx.pdf"
AP2 and AP3 would then be able to cite this source data in their index.xml leaf
element with:
xlink:href="../AP1/0004/m3/32body-data/32p-drug-prod/xxx.pdf"

Repeated Section & Location


Issues in Module 3
ICH Documents:
www.ich.org

For general FDA eCTD guidance see:


www.fda.gov/cder/regulatory/ersr/ectd.htm

CTDQ (M4Q)
CTDQ Questions and Answers
eCTD Specification
eCTD Questions and Answers

FDA Documents:
www.fda.gov/cder/guidance

Guidance for Industry: Drug Substance (Draft)


Guidance for Industry: Drug Product (Draft)
MaPP 5320.1 www.fda.gov/cder/mapp/5320.1.pdf

Repeated Quality Sections


See especially Electronic Common Technical
Document Specification, v 3.2, page 6-11
www.ich.org

Always use attributes when available, even for nonrepeating sections


Multiple drug substances (e.g. Augmentin)
Repeat entire, standalone drug substance section
Use name attribute
<m-3-2-s-drug-substance substance=amoxicillin manufacturer=ABC, Inc>

P.4 Control of Excipients


See eCTD Q&A

Topics Appearing in
Multiple Sections
A Few Examples

Note that information regarding P.2.x section may


be subject to change, pending the outcome of Q8

Drug Product Stability


P 2.1.1 Pharm Development (PD) Drug
Substance
Drug-drug, drug-excipient interactions

P 2.6 PD Compatibility
One-time compatibility with diluents / devices

P 8.3 Stability Studies


Stability protocol constitution / dilution

Components and Composition


P 1 Description and Composition of the
Drug Product
Unit dose

P 2.1.2 PD Excipients
Choice, amounts, impact on dp performance
Justification of ranges

P 2.2.1 PD Formulation Development


Clinical trial formulations

P 2.2.2 PD Overages

Components and Composition


(contd)
P 3.2 Batch Formula
P 4.1 to 4.6 Control of Excipients
R Regional Information
Batch records

Dissolution
P 2.1.1 PD Drug Substance
DP manufactured from different particle sizes

P 2.2.1 PD Formulation Development


Profiles linking clinical trial product to that
proposed for market

P 2.2.3 PD Physicochemical and


Biological Properties
Q6A disintegration rationale

Issues to be Resolved
Module 2 Quality Overall Summary
Content
Use
For supplements

P.2 Pharmaceutical Development (ICH Q8)


Incorporation of risk-management (ICH Q9)
Stability data

Outline

Historical FDA e-submission efforts


How to read the eCTD DTDs
Repeated sections
Location issues in Module 3
Topics appearing in multiple sections
Issues to be resolved

SECTION 1.7

Prequel Template or Guidance

This presentation provides advice on:


o Background/Motivation.
o ICH CTDGeneral guidance on summariesAnnex: granularity document.
o Module 2: Summaries.
o Mapping from the CFR .
o Module 4: Safety.

Prequel 1: Template or Guidance?

http://www.ich.org

Prequel 2: ICH and FDA

www.fda.gov (Big Hint: Sort by Date)

Guidance Compliant eCTDs:


Module 2: Summaries
Steve Wilson, DrPH, CAPT USPHS
Deputy Director, Division of Biometrics II, CDER/FDA

ICH Public Meeting


April 22, 2005
Doubletree Hotel and Executive Business Center
1750 Rockville Pike, Rockville, MD

Disclaimer
Views expressed in this presentation
are those of the speaker and not,
necessarily, of the Food and Drug
Administration

Outline
PART I
Background/Motivation
From the ICH CTD
General Guidance on Summaries
ANNEX : Granularity Document

Module 2: Summaries
Mapping from the CFR

PART II
Module 4: Safety
Questions & Answers (?)

Background/Motivation
Regulation, Guidance & Specifications
ICH Common Technical Document
eCTD Review Tools

Motivation: eCTD Review Tools


General Considerations for FDA Reviewers
Viewing an Electronic Table of Contents

View titles and headings in electronic TOC


Access documents directly from the
electronic table of contents to locate and
view the document.
Define own view for the layout
Define the types of documents displayed
in the TOC:
All documents, or
List current documents only

Guidance
Represents the Agencys current thinking
Not binding on FDA or the public
An alternative approach may be used if
such approach satisfies the requirements of
the applicable statutes, regulations or both.
Guidance does not limit the authority of a
Center and should not supplant

discussions between Centers and


sponsors.

S. Woollen

Regulation

Guidance

Example: NDA Regulation


Title 21 Food and Drugs

Chapter I Food and Drug Administration


Department of Health and Human Services
Subchapter D Drugs for Human Use
Part 314 Applications for FDA Approval to Market a
New Drug
Subpart B Applications
Sec. 31450 Content and format of an application
(c) Summary. (1) An application is required to contain a
summary of the application in enough detail that the
reader may gain a good general understanding of the
data and information in the application, including an
understanding of the quantitative aspects of the data..
www.fda.gov Code of Federal Regulations

Example: Guidance

From the ICH CTD


The CTD Pyramid
General Guidance on Summaries
ANNEX : Granularity Document

CTD Introduction

CTD Introduction: Module 2 -Summaries


CTD Table of Contents
2.1
CTD Introduction
2.2

Quality
Overall
Summary
2.3

Nonclinical
Overview
2.4
Nonclinical Written
And Tabulated
Summaries
2.6

Clinical
Overview
2.5

Clinical
l
Summary
i 2.7

ICH Harmonised Tripartite Guideline

Organisation of the Common Technical


Document for the Registration of
Pharmaceuticals for Human Use M4
Module 2. Common Technical Document
Summaries
Module 2 should begin with a general
introduction to the pharmaceutical,
pharmacologic class
mode of action
proposed clinical use.

In general, the Introduction should not


exceed one page.

Module 2 -- Summaries
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

The organisation of these summaries is


described in Guidelines for M4Q, M4S, and
M4E.

Content of CTD Summary:


Example -- Efficacy
Purpose --a critical analysis of the clinical data
pertinent to the efficacy of the product in the
intended population.
The analysis should consider all relevant data,
whether positive or negative, and should explain
why and how the data support the proposed
indication and prescribing information.
Those studies deemed relevant for evaluation of
efficacy should be identified, and reasons that
any apparently adequate and well- controlled
studies are not considered relevant should be
provided.
Prematurely terminated studies should be noted
and their impact considered.

M4: The CTD General Questions


and Answers: Granularity?
December 2004, ICH, Revision 3

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."

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?
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?

ANNEX : Granularity 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.

ANNEX : Granularity Document


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.

ANNEX : Granularity Document


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.

Granularity: Module 2 -- Summaries

Module 2: Summaries
2.1 Table of Contents (in XML backbone)
2.2 Introduction to summary
2.3 Quality overall summary
2.4 Non-clinical overview
2.5 Clinical overview
2.6 Non-clinical written and tabulated
summaries
2.7 Clinical summary

From the CTD Guidance

2.4 NON-CLINICAL OVERVIEW


The Non-clinical Overview should
provide an integrated overall analysis of
the information in the Common Technical
Document.
In general, the Nonclinical Overview
should not exceed about 30 pages.

Sample: eCTD TOC

2.6 Non-clinical written and


tabulated summaries
2.6.1 Introduction
2.6.2 Pharmacology written summary
2.6.3 Pharmacology tabulated summary
2.6.4 Pharmacokinetic written summary
2.6.5 Pharmacokinetic tabulated summary
2.6.6 Toxicology written summary
2.6.7 Toxicology tabulated summary

From the CTD Guidance

Content of Non-clinical Written


and Tabulated Summaries
2.6.1 Introduction
The aim of this section should be to introduce the
reviewer to the pharmaceutical and to its
proposed clinical use.
The following key elements should be covered:
Brief information concerning the pharmaceuticals
structure ( preferably, a structure diagram should be
provided) and pharmacologic properties.
Information concerning the pharmaceuticals proposed
clinical indication, dose, and duration of use.

2.6 Non-clinical written and


tabulated summaries
2.6.1 Introduction
2.6.2 Pharmacology written summary
2.6.3 Pharmacology tabulated summary
2.6.4 Pharmacokinetic written summary
2.6.5 Pharmacokinetic tabulated summary
2.6.6 Toxicology written summary
2.6.7 Toxicology tabulated summary

Sample: eCTD 2.6.5.5


Pharmacokinetics: Organ Distribution

2.7 Clinical Summary


2.7.1 Summary of Biopharmaceutic Studies
and Associated Analytical Methods
2.7.2 Summary of Clinical Pharmacology
Studies
2.7.3 Summary of Clinical Efficacy [indication]
2.7.4 Summary of Clinical Safety
2.7.5 References
2.7.6 Synopses of individual studies

Mapping from the Code of Federal


Regulations (CFR)
312. -- IND
314. -- NDA

Regulation

Guidance

Mapping Summaries: 312 -- IND


(3) Introductory statement and general
investigational plan.
(i) A brief introductory statement giving the name of
the drug and all active ingredients, the drugs
pharmacological class, the structural formula of the
drug (if known), the formulation of the dosage form(s)
to be used, the route of administration, and the broad
objectives and planned duration of the proposed
clinical investigation(s).
(ii) A brief summary of previous human experience
with the drug, with reference to other IND`s if
pertinent, and to investigational or marketing
experience in other countries that may be relevant to
the safety of the proposed clinical investigation(s).

Mapping Summaries: 312 -- IND


(iii) If the drug has been withdrawn from investigation or
marketing in any country for any reason related to safety or
effectiveness, identification of the country(ies) where the drug
was withdrawn and the reasons for the withdrawal.
(iv) A brief description of the overall plan for investigating the
drug product for the following year. The plan should include the
following:

(a) The rationale for the drug or the research study;


(b) the indication(s) to be studied;
(c) the general approach to be followed in evaluating the drug;
(d) the kinds of clinical trials to be conducted in the first year
following the submission (if plans are not developed for the entire
year, the sponsor should so indicate);
(e) the estimated number of patients to be given the drug in those
studies; and
(f) any risks of particular severity or seriousness anticipated on the
basis of the toxicological data in animals or prior studies in humans
with the drug or related drugs.

Mapping Summaries: 312. -- IND


CFR

eCTD

312.23(a)(3)(i)

Introductory statement

Introduction to
summary

312.23(a)(3)(iiiv)

Introductory statement

Clinical overall
summary

312.23(a)(8)

Pharmacology and
toxicology information

2.4 Nonclinical overview

312.23(a)(8)

Pharmacology and
toxicology information

2.6 Nonclinical written


and tabulated
summaries [use
appropriate sections]

312.23(a)(9)

Previous human
experience

2.7 Clinical summary


[use appropriate
sections]

2.6 Non-clinical written and


tabulated summaries
2.6.1 Introduction
2.6.2 Pharmacology written summary
2.6.3 Pharmacology tabulated summary
2.6.4 Pharmacokinetic written summary
2.6.5 Pharmacokinetic tabulated summary
2.6.6 Toxicology written summary
2.6.7 Toxicology tabulated summary

Mapping Summaries: 312. -- NDA


CFR

eCTD

314.50(c)(2)(ii) to
(ix)

Summaries

A.N.

Use the appropriate


sections

314.50(d)(7)

Pediatric use section

A.N.

Use appropriate
sections

314.60

Amendments to an
unapproved application

A. N. Use appropriate
sections

314.70 and 314.71

Supplements and other


changes to approved
applications

A.N.

Use appropriate
sections

314.96

Amendments to an
unapproved application

A.N

Use appropriate
sections
A.N. As Needed

Part 2
Guidances

SECTION 2

Guidance for Industry


M4 the CTD Efficacy
Questions and Answers

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 FDA. This guidance provides answers to
questions that have arisen since the finalization of the harmonized CTD guidance
documents. This guidance specifically addresses questions related to efficacy. Other
Q&A guidances are under development to address general questions as well as
questions related to quality and safety. The questions and answers provided here
reflect the consensus of the ICH parties.

Guidance for Industry


M4: The CTD Efficacy
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
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.
(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

Guidance for Industry1


M4: CTD Efficacy
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 specifically addresses questions related to efficacy. Other
question and answer (Q &A) guidances are under development to address general questions as
well as questions related to quality and safety. 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-Efficacy 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 .

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) M4: The CTD Quality, (3) M4:
The CTD Efficacy, and (4) M4: 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:

Clinical study reports contained in Module 5 are cited in the Clinical Overview and/or
the Clinical Summary in Module 2. Each clinical study report may be given a unique
short name when cited. Does the method of citing and naming have to be uniform
throughout all modules?

A1:

We recommend that each study have a unique short identifier that is used consistently
throughout the application. The applicant can select the identifier. The full title of the
study is provided in the Tabular Listing of All Clinical Studies (Section 5.2)

Q2:

Definitions/Terminology
What is the definition of Common Adverse Events as used in the CTD?

A2:

Guidance is provided by ICH E3 Guideline.

Q3:

Section Numbering/Title (in Module 5)


In Module 5 of the CTD, is it necessary to have a section number for each clinical
study report in a certain section, or is it enough just to mention the title:
5.3.5 Report of Efficacy.
5.3.5.1 Study Reports.
5.3.5.1.1 Placebo Controlled.
Study XXX

A3:

See ICH granularity document.

Contains Nonbinding Recommendations


Q4:

How many pages should a Clinical Summary be for an application that contains
multiple indications?

A4:

The estimated size of this document is 50-400 pages, assuming one indication.
Applications that include multiple indications will be larger, reflecting the submission of
multiple efficacy sections.

Q5:

Section 2.7.3.3 Comparisons and Analyses of Results Across Studies


The Guideline provides This section should also cross-reference important evidence
from Section 2, such as data that supports the dosage and administration section of the
labeling. However, this Guideline also provides a Section, 2.7.3.4. Analysis of
Clinical Information Relevant to Recommended Dose. Please specify how to
differentiate the two sections 2.7.3.3 and 2.7.3.4.

A5:

Section 2.7.3.3 summarizes the data across all studies that characterize efficacy of the
drug; Section 2.7.3.4 provides an integrated summary of the dose-response or blood
concentration-response relationships of effectiveness. In both cases, supportive data from
Section 2.7.2 can also be incorporated.

Q6:

Overall Extent of Exposure


In the Guideline, a table is required to be generated to present the overall extent of
drug exposure in all phases of the clinical development. Should the table include
patients alone or patients and healthy subjects?

A6:

That table should refer to all subjects exposed to at least one dose of the drug product.
Appropriate subsets of subjects relevant to the proposed indications should also be
identified and considered.

Q7:

Summary of Clinical Safety


Where should information be described concerning the validity of extrapolation of
foreign clinical safety data to a new region?

A7:

Summaries of any bridging studies using clinical endpoints (i.e., certain studies intended
to evaluate the ability to extrapolate certain types of foreign clinical data to the new
region (see ICH E5)) should be included in Section 2.7.3.2. Where appropriate, such
information should also be described in the summarization of safety data as related to
intrinsic and extrinsic ethnic factors (ICH E5), in Sections 2.7.4.5.1 and 2.7.4.5.2.
Finally, some applications might include in Section 5.3.5.3 a detailed analysis of
bridging, considering formal bridging studies, other relevant clinical studies, and other

Contains Nonbinding Recommendations


appropriate information. Such information should be included in that detailed analysis of
bridging.
Q8:

Bioavailability/Bioequivalence Study Data


Where should the information on bioequivalence studies for a generic application be
included?

A8:

Bioavailability study reports should be included in Module 5 (Clinical documentation),


under section 5.3.1 Reports of Biopharmaceutical Studies. More specifically, reports
of comparative Bioavailability/Bioequivalence studies should go under section 5.3.1.2.

Q9:

Tabular Listing of Clinical Studies in Paper CTD


In Module 5, 5.2 is denoted as the Tabular Listing of all Clinical Studies. Is this
section for a summary listing of all clinical studies in the submission, or it is for the
listing of the individual study reports? In other words, should the listings from the
appendices of the individual study reports be included here, rather than as an appendix
to the CSR, or are these only listings that summarize all studies?

A9:

The tabular listing described in section 5.2 is a listing of all clinical studies in the
submission.
An example of such a listing is given in Table 5.1.

Q10

Integrated Summary of Safety and Effectiveness


Does the CTD section on safety in Module 2 replace the section under 21 CFR
314.50(d)(5)(v)-(vi) calling for integrated summary of safety and effectiveness
(ISS/ISE)?

A10:

The ISS/ISE are critical components of the safety and effectiveness submission and are
expected to be submitted in the application in accordance with the regulation. FDAs
guidance Format and Content of Clinical and Statistical Sections of Application gives
advice on how to construct these summaries. Note that, despite the name, these are
integrated analyses of all relevant data, not summaries.
The Clinical Safety sections of the CTD follow approximately the outline of the sections
of the ISS/ISE, although they are somewhat modified by experience with ICH E-3
(Structure and Content of Clinical Study Reports). The CTD Clinical Overview and
Summary in Module 2 will not usually contain the level of detail expected for an ISS. It
may contain the level of detail needed for an ISE, but this would need to be determined
on a case-by-case basis.

Contains Nonbinding Recommendations

If the requirements of 21 CFR 314.50 can be met for a particular application by what is in
the CTD Module 2 summary, the CTD Module 2 section would fulfill the need for an
ISS/ISE. In some cases, it will be convenient to write much of what is needed in the
CTD Module 2 with appropriate appendices in Module 5. In other cases, the ISS/ISE
would be summarized in Module 2, with detailed reports in Module 5.
Any questions about these matters can be raised with the reviewing division.
Q11: Microbiology Data
The microbiology data will include both in vitro and in vivo studies. Where should the
microbiology summary, overview, and study reports be included?
A11:

The microbiology data from both in vitro and in vivo studies should be included with the
Efficacy information. The summary information should be provided in the appropriate
section 2.7 Clinical Summary and the reports should be filed in section 5.3.5.4 Other
Study Reports.
In addition, the microbiology information can be described in the Nonclinical sections as
appropriate.

Q12: Clinical Variation


For a clinical variation application, is it mandatory to submit a clinical overview and a
clinical summary, or is it acceptable to submit either only an overview or only a
summary? What are the parameters/conditions to be taken into account for choosing
one or the other approach?
A12:

Since variation is a term from the EU regulations, the answer should be provided by the
EMEA.

Q13: Integrated Analysis of Efficacy (ISE) Section 2.7 Clinical Summary Statistical
Listings
What approach should applicants take for the formatting and presentation of their
integrated analyses when they have large amounts of statistical output to present
(several thousands of pages)?
A13:

As stated in section Reports of Analyses From More Than One Study 5.3.5.3, where the
details of the analysis are too extensive to be reported in a summary document (for
example, section Clinical Summary 2.7), they should be presented in a separate report.
Such report should be placed in section 5.3.5.3.

Contains Nonbinding Recommendations

Q14: 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? (The
section name is in many cases too long to indicate in a cross string.)
A14:

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.

Q15: Limitations of the Safety Database and Potential Implications


Section 2.5 Clinical Overview and section 2.5.5 Overview of Safety both refer to an
assessment of the limitations of the safety database but give few details on how to
describe them. How should these limitations be described? In addition, there is no
specific reference to any postmarketing steps the applicant can take to remedy those
limitations. Where should a discussion of any postmarketing pharmacovigilance and
other postmarketing study plans go?
A15:

A fuller discussion of how to describe in the CTD the limitations of the safety database
and the potential implications for the safety of the drug when marketed is as follows:

Nonclinical toxicology and safety pharmacology concerns, such as those arising from
reproductive / developmental toxicity, carcinogenicity, hepatic injury, central nervous
system injury, or effects on cardiac repolarization that are not fully resolved by
available human data, or that arise from incomplete testing.

Limitations of human safety database, such as:


o Patient selection criteria that excluded people who are likely to be candidates for
treatment in medical practice.
o Evaluations that were deficient for certain purposes (e.g., many drugs with
sedative properties are not evaluated for effects on cognitive function in the
elderly).
o Limited exposure of demographic or other subgroups, such as children, women,
the elderly, or patients with abnormal hepatic or renal function.

Contains Nonbinding Recommendations

Identified adverse events and potential adverse events that require further
characterization or evaluation with respect to frequency and/or seriousness in the
general population or in specific subgroups.

Important potential risks (e.g., known risks of pharmacologically related drugs) that
require further evaluation.

Drug-drug interactions that have not been assessed adequately.

Such information should be described and discussed in section 2.5.5 Overview of Safety,
with appropriate cross references to section 2.7.4 Summary of Clinical Safety and any
other relevant sections.
A discussion of any planned postmarketing activity or study to address the limitations of
the premarketing safety database should also be included in section 2.5.5 Overview of
Safety, with any protocols for specific studies provided in section5.3.5.4 Other Clinical
Study Reports or other sections as appropriate (e.g., module 4 if the study is a nonclinical
study).
An ICH guideline (E2E Pharmacovigilance Planning) is being developed to further
address the question of how to describe the safety data and its limitations and how to
describe planned postmarketing activities and studies.
Q16: Multiple Indications
When submitting one dossier for multiple indications, how should the applicant
present them in the clinical part of the registration dossier, for example sections 2.5
Clinical Overview, 2.7.3 Summary of Clinical Efficacy, and 5.3.5 Reports of Efficacy
and Safety Studies?
A16:

One section 2.5 Clinical Overview is recommended for multiple indications to be


registered along with development rationale and cross-referencing to the corresponding
2.7.3 and 5.3.5 sections; the benefit/risk conclusions should support corresponding
claimed indications.
For section 2.7.3 Summary of Clinical Efficacy, in the case of more than one indication,
the following organization is recommended as applicable. The current CTD numbering
should be retained with identification of the indication, for example:
2.7.3. UTI Summary of Clinical Efficacy
2.7.3.1. UTI Background
2.7.3.2. UTI Summary of Results of individual studies
2.7.3.3. UTI comparison and analysis
2.7.3.3.1. UTI study population
2.7.3.3.2. UTI Comparison of efficacy results
2.7.3. Pneumonia Summary of Clinical Efficacy
2.7.3.1. Pneumonia Background
Other sections follow the same organization where applicable.

Contains Nonbinding Recommendations


For section 5.3.5 Reports of Efficacy and Safety Studies, in case of more than one
indication, the following organization is recommended as applicable. The current CTD
numbering should be retained with identification of the indications, for example:
5.3.5.UTI
5.3.5.1. UTI Controlled studies
5.3.5.2. UTI Uncontrolled studies
5.3.5. Pneumonia
5.3.5.1. Pneumonia Controlled studies
5.3.5.2. Pneumonia Uncontrolled studies
Other sections follow the same organization, where applicable.
Q17: Narrative Descriptions
The CTD guidance for Section Overall Safety Evaluation Plan and Narratives of
Safety Studies 2.7.4.1.1 states that narrative descriptions for studies that contributed
both efficacy and safety should be included in Section Summary of Results of
Individual Studies 2.7.3.2 and only referenced in the safety section. Please clarify
whether the narrative to be included in 2.7.3.2 should include the safety results as well
as enough detail to allow the reviewer to understand the exposure and how safety
data were collected or whether the results should be included in Section 2.7.4.1.1.
A17:

In general, safety results should be described in section 2.7.4.1.1, because section


Summary of Clinical Efficacy 2.7.3 is devoted to efficacy. To avoid the need to describe
the same study twice, section 2.7.3.2 asks for a reasonably complete description of
studies pertinent to both safety and efficacy, including, in study narratives, information
about the extent of exposure of study subjects to the test drug and how safety data were
collected. This approach is confirmed in section 2.7.4.1.1, which notes that narratives for
studies contributing both safety and efficacy data should be included in section 2.7.3.2.
As noted in section Background and Overview of Clinical Efficacy 2.7.3.1, however, any
results of these studies that are pertinent to evaluation of safety should be discussed in
section Summary of Clinical Safety 2.7.4.

Q18: According to ICH E3 Structure and Content of Clinical Study Reports, the case report
forms should be located in Appendix 16.3, the individual patient data listings in
Appendix 16.4, and the publications and literature references in Appendices 16.1.11
and 16.1.12 respectively. The CTD organization provides locations for case report
forms and individual patient data listings in Module 5.3.7 and for literature references
in Module 5.4.
Can clarity be provided as to where these items should actually be placed in CTD and
the eCTD submissions?
A18:

For paper submissions, case report forms and individual patient data listings should be
located in Module 5.3.7, identified by study.

Contains Nonbinding Recommendations

For eCTD, PDF files for case report forms and individual patient data listings should be
organized by study in the folder for Module 5.3.7. However, in the index.xml file, the
leaf elements for the case report forms and individual patient data listings should be
included under the same heading as other study report files with additional information
included with any accompanying study tagging file. In addition, a repeat of the leaf
element can be placed under the heading 5.3.7 Case Report Forms and Individual Patient
Data Listings. Datasets, if required by the region, should be organized according to
regional guidance.
For paper submissions, publications and literature references should be located in Module
5.4.
For eCTD, the files for publications and literature references should be located in the
folder for Module 5.4. However, in the index.xml file, the leaf elements for the
publications and literature references should be included under the same heading as other
study report files with additional information included with any accompanying study
tagging file. In addition, a repeat of the leaf element should be placed under the heading
for 5.4 Literature References.

SECTION 3

Guidance for Industry


Structure and Content of Clinical
Study Reports

The objective of this guideline is to facilitate the compilation of a single core clinical
study report acceptable to all regulatory authorities of the ICH regions. The regulatory
authority-specific additions will consist of modules to be considered as appendices,
available upon request according to regional regulatory requirements.

Table of Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.

TITLE PAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2.

SYNOPSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

3.

TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY REPORT

4.

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

5.

ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) . . . . .
5.2
Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3
Patient Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.

INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

7.

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

8.

STUDY OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

9.

INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
9.1
Overall Study Design and Plan: Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
9.2
Discussion of Study Design, Including the Choice of Control Groups . . . . . . . . . 7
9.3
Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.3.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.3.2 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.3.3 Removal of Patients From Therapy or Assessment . . . . . . . . . . . . . . . . . 9
9.4
Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.4.1 Treatments Administered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.4.2 Identity of Investigational Products(s) . . . . . . . . . . . . . . . . . . . . . . . . . . 10
9.4.3 Method of Assigning Patients to Treatment Groups . . . . . . . . . . . . . . . 10
9.4.4 Selection of Doses in the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
9.4.5 Selection and Timing of Dose for Each Patient . . . . . . . . . . . . . . . . . . . 11
9.4.6 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
9.4.7 Prior and Concomitant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
9.4.8 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
9.5
Efficacy and Safety Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart . . . . . . . . . 12
9.5.2 Appropriateness of Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
9.5.3 Primary Efficacy Variable(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
i

...5

................. 5
5
5
5
5

............ 5

9.6
9.7
9.8

9.5.4 Drug Concentration Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . .


Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Statistical Methods Planned in the Protocol and Determination of Sample
Size
9.7.2 Statistical and Analytical Plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.7.2 Determination of Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Changes in the Conduct of the Study or Planned Analyses . . . . . . . . . . . . . . . .

14
14
15
15
15
16

10.

STUDY PATIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
10.1 Disposition of Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
10.2 Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

11.

EFFICACY EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1 Data Sets Analyzed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2 Demographic and Other Baseline Characteristics . . . . . . . . . . . . . . . . . . . . . . .
11.3. Measurements of Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4 Efficacy Results and Tabulations of Individual Patient Data . . . . . . . . . . . . . . .
11.4.1 Analysis of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4.2 Statistical/Analytical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4.2.1
Adjustments for Covariates . . . . . . . . . . . . . . . . . . . . . .
11.4.2.2
Handling of Dropouts or Missing Data . . . . . . . . . . . . . .
11.4.2.3
Interim Analyses and Data Monitoring . . . . . . . . . . . . . .
11.4.2.4
Multicenter Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4.2.5
Multiple Comparisons/Multiplicity . . . . . . . . . . . . . . . . .
11.4.2.6
Use of an Efficacy Subset of Patients . . . . . . . . . . . . .
11.4.2.7
Active-Control Studies Intended to Show Equivalence . .
11.4.2.8
Examination of Subgroups . . . . . . . . . . . . . . . . . . . . . . .
11.4.3 Tabulation of Individual Response Data . . . . . . . . . . . . . . . . . . . . . . . .
11.4.4 Drug Dose, Drug Concentration, and Relationships to Response . . . . . .
11.4.5 Drug-Drug and Drug-Disease Interactions . . . . . . . . . . . . . . . . . . . . . .
11.4.6 By-Patient Displays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4.7 Efficacy Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17
17
18
19
19
19
20
20
21
21
22
22
22
23
23
23
24
25
25
25

12.

SAFETY EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.1 Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2.1 Brief Summary of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2.2 Display of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2.3 Analysis of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2.4 Listing of Adverse Events by Patient . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.3. Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
.
12.3.1 Listing of Deaths, Other Serious Adverse Events, and Other Significant
Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.3.1.1
Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25
26
27
27
27
29
29
30

ii

30
31

12.4

12.5.
12.6

12.3.1.2
Other Serious Adverse Events . . . . . . . . . . . . . . . . . . . .
12.3.1.3
Other Significant Adverse Events . . . . . . . . . . . . . . . . . .
12.3.2 Narratives of Deaths, Other Serious Adverse Events, and Certain Other
Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse Events, and
Other Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.4.1 Listing of Individual Laboratory Measurements by Patient (Appendix
16.2.8) and Each Abnormal Laboratory Value (see section 14.3.4) . . . .
12.4.2 Evaluation of Each Laboratory Parameter . . . . . . . . . . . . . . . . . . . . . . .
12.4.2.1
Laboratory Values Over Time . . . . . . . . . . . . . . . . . . . .
12.4.2.2
Individual Patient Changes . . . . . . . . . . . . . . . . . . . . . . .
12.4.2.3.
Individual Clinically Significant Abnormalities . . . . . . . .
Vital Signs, Physical Findings, and Other Observations Related to Safety . . . . .
Safety Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31
31
31
32
32
32
33
33
34
34
35
35

13.

DISCUSSION AND OVERALL CONCLUSIONS

14.

TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE


TEXT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
14.1 Demographic Data Summary figures and tables.
. . . . . . . . . . . . . . . . . . . . . . . 36
14.2 Efficacy Data Summary figures and tables. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
14.3 Safety Data Summary figures and tables. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
14.3.1 Displays of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events
. . . . 36
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse
Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
14.3.4 Abnormal Laboratory Value Listing (each patient) . . . . . . . . . . . . . . . . 36

15.

REFERENCE LIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

16.

APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1 Study Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.1 Protocol and protocol amendments. . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.2 Sample case report form (unique pages only).
. . . . . . . . . . . . . . . . . . . 37
16.1.3 List of IEC's or IRB's (plus the name of the committee chair if required by
the regulatory authority) and representative written information for patient
and sample consent forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.4 List and description of investigators and other important participants in the
study, including brief (one page) CV's or equivalent summaries of training
and experience relevant to the performance of the clinical study.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.5 Signatures of principal or coordinating investigator(s) or sponsor's
iii

. . . . . . . . . . . . . . . . . . . . . . . . . . . 35

16.2

16.3.

16.4

responsible medical officer, depending on the regulatory authority's


requirement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.6 Listing of patients receiving test drug(s)/investigational product(s) from
specific batches, where more than one batch was used. . . . . . . . . . . . . . 37
16.1.7 Randomization scheme and codes (patient identification and treatment
assigned). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.8 Audit certificates (if available). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.9 Documentation of statistical methods. . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.10Documentation of inter-laboratory standardization methods and quality
assurance procedures if used. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.11Publications based on the study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.1.12Important publications referenced in the report. . . . . . . . . . . . . . . . . . . 38
Patient Data Listings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.2.1 Discontinued patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.2.2 Protocol deviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.2.3 Patients excluded from the efficacy analysis. . . . . . . . . . . . . . . . . . . . . . 38
16.2.4 Demographic data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.2.5 Compliance and/or drug concentration data (if available). . . . . . . . . . . . 38
16.2.6 Individual efficacy response data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.2.7 Adverse event listings (each patient). . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.2.8 Listing of individual laboratory measurements by patient, when required by
regulatory authorities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Case Report Forms (CRF's) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.3.1 CRF's for deaths, other serious adverse events, and withdrawals for
adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
16.3.2 Other CRF's submitted. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Individual Patient Data Listings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

SYNOPSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Annex I

PRINCIPAL OR COORDINATING INVESTIGATOR(S) OR SPONSORS RESPONSIBLE


MEDICAL OFFICER (EXAMPLE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Annex II
STUDY DESIGN AND SCHEDULE OF ASSESSMENTS (EXAMPLE)

. . . . . . . . Annex IIIa

STUDY DESIGN AND SCHEDULE OF ASSESSMENTS (EXAMPLE)

. . . . . . . . Annex IIIb

DISPOSITION OF PATIENTS (EXAMPLE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Annex IVa


DISPOSITION OF PATIENTS (EXAMPLE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Annex IVb
LISTING OF PATIENTS WHO DISCONTINUED THERAPY (EXAMPLE)

iv

. . . . . . . Annex V

LISTING OF PATIENTS AND OBSERVATIONS EXCLUDED FROM EFFICACY


ANALYSIS (EXAMPLE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Annex VI
NUMBER OF PATIENTS EXCLUDED FROM EFFICACY ANALYSIS
(EXAMPLE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Annex VII

GUIDANCE FOR SECTION 11.4.2 - STATISTICAL/ANALYTICAL ISSUES AND


APPENDIX 16.1.9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Annex VIII

GUIDELINE FOR INDUSTRY 1


STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS
TABLE OF CONTENTS
INTRODUCTION
The objective of this guideline is to facilitate the compilation of a single core clinical study report
acceptable to all regulatory authorities of the ICH regions. The regulatory authority-specific
additions will consist of modules to be considered as appendices, available upon request according
to regional regulatory requirements.
The clinical study report described in this guideline is an integrated full report of an individual
study of any therapeutic, prophylactic, or diagnostic agent (referred to herein as drug or
treatment) conducted in patients. The clinical and statistical description, presentations, and
analyses are integrated into a single report, incorporating tables and figures into the main text of
the report or at the end of the text, with appendices containing such information as the protocol,
sample case report forms, investigator-related information, information related to the test
drugs/investigational products including active control/comparators, technical statistical
documentation, related publications, patient data listings, and technical statistical details such as
derivations, computations, analyses,and computer output. The integrated full report of a study
should not be derived by simply joining a separate clinical and statistical report. Although this
guideline is mainly aimed at efficacy and safety trials, the basic principles and structure described
can be applied to other kinds of trials, such as clinical pharmacology studies. Depending on the
nature and importance of such studies, a less detailed report might be appropriate.

The guideline is intended to assist sponsors in the development of a report that is complete, free
from ambiguity, well organized, and easy to review. The report should provide a clear explanation
1

This guideline was developed within the Expert Working Group (Efficacy) 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, November 29, 1995. At Step 4 of the process, the final
draft is recommended for adoption to the regulatory bodies of the European Union, Japan and the USA. This guideline
was published in the Federal Register on July 17, 1996 (61 FR 37320) and is applicable to drug and biological
products. Although this guideline does not create or confer any rights for or on any person and does not operate to bind
FDA or the industry, it does represent the Agencys current thinking on structure and content of clincial study reports.
For additional copies of this guideline, contact the Drug Information Branch, HFD-210, CDER, FDA, 5600 Fishers
Lane, Rockville, MD 20857 (Phone: 301-827-4573) or the Manufacturers Assistance and Communication Staff (HFM42), CBER, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed adhesive label to assist
the offices in processing your request. An electronic version of this guidance is also available via Internet using the
World Wide Web (WWW) (connect to the CDER Home Page at WWW.FDA.GOV/CDER and go to the Regulatory
Guidance section).

of how the critical design features of the study were chosen and enough information on the plan,
methods, and conduct of the study so that there is no ambiguity in how the study was carried out.
The report with its appendices should also provide enough individual patient data, including the
demographic and baseline data, and details of analytical methods, to allow replication of the
critical analyses when authorities wish to do so. It is also particularly important that all analyses,
tables, and figures carry, in text or as part of the table, clear identification of the set of patients
from which they were generated.
Depending on the regulatory authority's review policy, abbreviated reports using summarized data
or with some sections deleted may be acceptable for uncontrolled studies or other studies not
designed to establish efficacy, for seriously flawed or aborted studies, or for controlled studies
that examine conditions clearly unrelated to those for which a claim is made. A controlled safety
study, however, should be reported in full. If an abbreviated report is provided, a full description
of safety aspects should be included in all cases. If an abbreviated report is submitted, there should
be enough detail of design and results to allow the regulatory authority to determine whether a
full report is needed. If there is any question regarding whether the reports are needed, it may be
useful to consult the regulatory authority.
In presenting the detailed description of how the study was carried out, it may be possible simply
to restate the description in the initial protocol. Often, however, it is possible to present the
methodology of the study more concisely in a separate document. In each section describing the
design and conduct of the study, it is particularly important to clarify features of the study that are
not well-described in the protocol and identify ways in which the study as conducted differed from
the protocol, and to discuss the statistical methods and analyses used to account for these
deviations from the planned protocol.
The full integrated report of the individual study should include the most detailed discussion of
individual adverse events or laboratory abnormalities, but these should usually be reexamined as
part of an overall safety analysis of all available data in any application.
The report should describe demographic and other potentially predictive characteristics of the
study population and, where the study is large enough to permit this, present data for
demographic (e.g., age, sex, race, weight) and other (e.g., renal or hepatic function) subgroups so
that possible differences in efficacy or safety can be identified. Usually, however, subgroup
responses should be examined in the larger data base used in the overall analysis.
The data listings requested as part of the report (usually in an appendix) are those needed to
support critical analyses. Data listings that are part of the report should be readily usable by the
reviewer. Thus, although it may be desirable to include many variables in a single listing to limit
size, this should not be at the expense of clarity. An excess of data should not be allowed to lead
to, for example, overuse of symbols instead of words or easily understood abbreviations, or to
too-small displays. In this case, it is preferable to produce several listings.

Data should be presented in the report at different levels of detail: Overall summary figures and
tables for important demographic, efficacy, and safety variables may be placed in the text to
illustrate important points; other summary figures, tables, and listings for demographic, efficacy,
and safety variables should be provided in section 14; individual patient data for specified groups
of patients should be provided as listings in Appendix 16.2; and all individual patient data
(archival listings requested only in the United States) should be provided in Appendix 16.4.
In any table, figure, or data listing, estimated or derived values, if used, should be identified in a
conspicuous fashion. Detailed explanations should be provided as to how such values were
estimated or derived and what underlying assumptions were made.
The guidance provided below is detailed and is intended to notify the applicant of virtually all of
the information that should routinely be provided so that postsubmission requests for further data
clarification and analyses can be reduced as much as possible. Nonetheless, specific requirements
for data presentation and/or analysis may depend on specific situations, may evolve over time,
may vary from drug class to drug class, may differ among regions, and cannot be described in
general terms. It is, therefore, important to refer to specific clinical guidelines and to discuss data
presentation and analyses with the reviewing authority, whenever possible. Detailed written
guidance on statistical approaches is available from some authorities.
Each report should consider all of the topics described (unless clearly not relevant) although the
specific sequence and grouping of topics may be changed if alternatives are more logical for a
particular study. Some data in the appendices are specific requirements of individual regulatory
authorities and should be submitted as appropriate. The numbering should then be adapted
accordingly.
In the case of very large trials, some of the provisions of this guideline may be impractical or
inappropriate. When planning and when reporting such trials, contact with regulatory authorities
to discuss an appropriate report format is encouraged.
The provisions of this guideline should be used in conjunction with other ICH guidelines.
1.

TITLE PAGE

The title page should contain the following information:


Study title.
Name of test drug/investigational product.
Indication studied.
If not apparent from the title, a brief (one to two sentences) description giving design
3

(parallel, cross-over, blinding, randomized) comparison (placebo, active, dose/response),


duration, dose, and patient population.
Name of the sponsor.
Protocol identification (code or number).
Development phase of study.
Study initiation date (first patient enrolled, or any other verifiable definition).
Date of early study termination, if any.
Study completion date (last patient completed).
Name and affiliation of principal or coordinating investigator(s) or sponsor's responsible
medical officer.
Name of company/sponsor signatory (the person responsible for the study report within
the company/sponsor). The name, telephone number, and fax number of the
company/sponsor contact persons for questions arising during review of the study report
should be indicated on this page or in the letter of application.
Statement indicating whether the study was performed in compliance with good clinical
practice (GCP), including the archiving of essential documents.
Date of the report (identify any earlier reports from the same study by title and date).
2.

SYNOPSIS

A brief synopsis (usually limited to three pages) that summarizes the study should be provided
(see Annex I of the guideline for an example of a synopsis format used in Europe). The synopsis
should include numerical data to illustrate results, not just text or p-values.

3.
TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY
REPORT
The table of contents should include:

The page number or other locating information of each section, including summary tables,
figures, and graphs.
A list and the locations of appendices, tabulations, and any case report forms provided.
4.

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

A list of the abbreviations, and lists and definitions of specialized or unusual terms or
measurement units used in the report should be provided. Abbreviated terms should be spelled out
and the abbreviation indicated in parentheses at first appearance in the text.
5.

ETHICS
5.1

Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

It should be confirmed that the study and any amendments were reviewed by an IEC or
IRB. A list of all IEC's or IRB's consulted should be given in Appendix 16.1.3 and, if
required by the regulatory authority, thename of the committee Chair should be provided.
5.2

Ethical Conduct of the Study

It should be confirmed that the study was conducted in accordance with the ethical
principles that have their origins in the Declaration of Helsinki.
5.3

Patient Information and Consent

How and when informed consent was obtained in relation to patient enrollment (e.g., at
allocation, prescreening) should be described.
Representative written information for the patient (if any) and a sample of the patient
consent form used should be provided in Appendix 16.1.3.
6.

INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

The administrative structure of the study (e.g., principal investigator, coordinating investigator,
steering committee, administration, monitoring and evaluation committees, institutions,
statistician, central laboratory facilities, contract research organization (C.R.O.), clinical trial
supply management) should be described briefly in the body of the report.
There should be provided in Appendix 16.1.4 a list of the investigators with their affiliations, their
role in the study, and their qualifications (curriculum vitae or equivalent). A similar list for other
persons whose participation materially affected the conduct of the study should also be provided
in Appendix 16.1.4. In the case of large trials with many investigators, the above information may
5

be abbreviated to consist of general statements of qualifications for persons carrying out particular
roles in the study with only the name, degree, and institutional affiliation and roles of each
investigator or other participant.
The listing should include:
A.

Investigators.

B.
Any other person carrying out observations of primary or other major efficacy
variables, such as a nurse, physician's assistant, clinical psychologist, clinical pharmacist,
or house staff physician. It is not necessary to include in this list a person with only an
occasional role, e.g., an on-call physician who dealt with a possible adverse effect or a
temporary substitute for any of the above.
C.

The author(s) of the report, including the responsible biostatistician(s).

Where signatures of the principal or coordinating investigators are required by regulatory


authorities, these should be included in Appendix 16.1.5 (see Annex II for a sample form).
Where these are not required, the signature of the sponsor's responsible medical officer
should be provided in Appendix 16.1.5.
7.

INTRODUCTION

The introduction should contain a brief statement (maximum: one page) placing the study in the
context of the development of the test drug/investigational product, relating the critical features of
the study (e.g., rationale and aims, target population, treatment, duration, primary endpoints) to
that development. Any guidelines that were followed in the development of the protocol or any
other agreements/meetings between the sponsor/company and regulatory authorities that are
relevant to the particular study should be identified or described.
8.

STUDY OBJECTIVES

A statement describing the overall purpose(s) of the study should be provided.

9.

INVESTIGATIONAL PLAN
9.1

Overall Study Design and Plan: Description

The overall study plan and design (configuration) of the study (e.g., parallel, cross-over)
should be described briefly but clearly, using charts and diagrams as needed. If other
6

studies used a very similar protocol, it may be useful to note this and describe any
important differences. The actual protocol and any changes should be included as
Appendix 16.1.1 and a sample case report form (unique pages only; i.e., it is not necessary
to include identical pages from forms for different evaluations or visits) as Appendix
16.1.2. If any of the information in this section comes from sources other than the
protocol, these should be identified.
The information provided should include:
Treatments studied (specific drugs, doses, and procedures).
Patient population studied and the number of patients to be included.
Level and method of blinding/masking (e.g., open, double-blind, single-blind,
blinded evaluators, and unblinded patients and/or investigators).
Kind of control(s) (e.g., placebo, no treatment, active drug, dose-response,
historical) and study configuration (parallel, cross-over).
Method of assignment to treatment (randomization, stratification).
Sequence and duration of all study periods, including prerandomization and
post-treatment periods, therapy withdrawal periods, and single and double-blind
treatment periods. When patients were randomized should be specified. It is
usually helpful to display the design graphically with a flow chart that includes
timing of assessments (see Annexes IIIa and IIIb for an example).
Any safety, data monitoring, or special steering or evaluation committees.
Any interim analyses.
9.2

Discussion of Study Design, Including the Choice of Control Groups

The specific control chosen and the study design used should be discussed, as necessary.
Examples of design issues meriting discussion follow.
Generally, the control (comparison) groups that are recognized are placebo concurrent
control, no treatment concurrent control, active treatment concurrent control, dose
comparison concurrent control, and historical control. In addition to the type of control,
other critical design features that may need discussion are use of a cross-over design and
selection of patients with particular prior history, such as response or nonresponse to a
specific drug or member of a drug class. If randomization was not used, it is important to
explain how other techniques, if any, guarded against systematic selection bias.
7

Known or potential problems associated with the study design or control group chosen
should be discussed in light of the specific disease and therapies being studied. For a
cross-over design, for example, there should be consideration, among other things, of the
likelihood of spontaneous change in the disease and of carry-over effects of treatment
during the study.
If efficacy was to be demonstrated by showing equivalence, i.e., the absence of a specified
degree of inferiority of the new treatment compared to an established treatment, problems
associated with such study designs should be addressed. Specifically, there should be
provided a basis for considering the study capable of distinguishing active from inactive
therapy. Support may be provided by an analysis of previous studies similar to the present
study with respect to important design characteristics (e.g., patient selection, study
endpoints, duration, dose of active control, concomitant therapy) showing a consistent
ability to demonstrate superiority of the active control to placebo. How to assess the
ability of the present study to distinguish effective from ineffective therapy should also be
discussed. For example, it may be possible to identify a treatment response (based on past
studies) that would clearly distinguish between the treated population and an untreated
group. Such a response could be the change of a measure from baseline or some other
specified outcome like healing rate or survival rate. Attainment of such a response would
support the expectation that the study could have distinguished the active drug from an
inactive drug. There should also be a discussion of the degree of inferiority of the therapy
(often referred to as the delta value) the study was intended to show was not exceeded.
The limitations of historical controls are well known (e.g., difficulty of assuring
comparability of treated groups, inability to blind investigators to treatment, change in
therapy/disease, difference due to placebo effect) and deserve particular attention.
Other specific features of the design may also deserve discussion, including presence or
absence of washout periods and the duration of the treatment period, especially for a
chronic illness. The rationale for dose and dose-interval selection should be explained, if it
is not obvious. For example, once daily dosing with a short half-life drug whose effect is
closely related in time to blood level is not usually effective; if the study design uses such
dosing, this should be explained, e.g., by pointing to pharmacodynamic evidence that
effect is prolonged compared to blood levels. The procedures used to seek evidence of
escape from drug effect at the end of the dose-interval, such as measurements of effect
just before dosing, should be described. Similarly, in a parallel design dose-response study,
the choice of doses should be explained.
9.3

Selection of Study Population


9.3.1

Inclusion Criteria

The patient population and the selection criteria used to enter the patients into the
8

study should be described, and the suitability of the population for the purposes of
the study discussed. Specific diagnostic criteria used, as well as specific
disease(e.g., disease of a particular severity or duration, results of a particular test
or rating scale(s) or physical examination, particular features of clinical history,
such as failure or success on prior therapy, or other potential prognostic factors
and any age, sex, or ethnic factors) should be presented.
Screening criteria and any additional criteria for randomization or entry into the
test drug/investigational product treatment part of the trial should be described. If
there is reason to believe that there were additional entry criteria, not defined in the
protocol, the implications of these should be discussed. For example, some
investigators may have excluded or entered into other studies patients who were
particularly ill or who had particular baseline characteristics.
9.3.2

Exclusion Criteria

The criteria for exclusion at entry into the study should be specified and the
rationale provided (e.g., safety concerns, administrative reasons, or lack of
suitability for the trial). The impact of exclusions on the generalizability of the
study should be discussed in section 13 of the study report or in an overview of
safety and efficacy.
9.3.3

Removal of Patients From Therapy or Assessment

The predetermined reasons for removing patients from therapy or assessment


observation, if any, should be described, as should the nature and duration of any
planned followup observations in those patients.
9.4

Treatments
9.4.1

Treatments Administered

The precise treatments or diagnostic agents to be administered in each arm of the


study, and for each period of the study, should be described including route and
mode of administration, dose, and dosage schedule.
9.4.2

Identity of Investigational Products(s)

In the text of the report, a brief description of the test drug(s)/investigational


product(s) (formulation, strength, batch number(s)) should be given. If more than
one batch of test drug/investigational product was used, patients receiving each
batch should be identified in Appendix 16.1.6.

The source of placebos and active control/comparator product(s) should be


provided. Any modification of comparator product(s) from their usual commercial
state should be noted, and the steps taken to assure that their bioavailability was
unaltered should be described.
For long-duration trials of investigational products with limited shelf-lives or
incomplete stability data, the logistics of resupply of the materials should be
described. Any use of test materials past their expiry date should be noted, and
patients receiving them identified. If there were specific storage requirements,
these should also be described.
9.4.3

Method of Assigning Patients to Treatment Groups

The specific methods used to assign patients to treatment groups, e.g., centralized
allocation, allocation within sites, adaptive allocation (that is, assignment on the
basis of earlier assignment or outcome) should be described in the text of the
report, including any stratification or blocking procedures. Any unusual features
should be explained.
A detailed description of the randomization method, including how it was
executed, should be given in Appendix 16.1.7 with references cited if necessary. A
table exhibiting the randomization codes, patient identifier, and treatment assigned
should also be presented in the Appendix. For a multicenter study, the information
should be given by center. The method of generating random numbers should be
explained.
For a historically controlled trial, it is important to explain how the particul ar
control was selected and what other historical experiences were examined, if any,
and how their results compared to the control used.
9.4.4

Selection of Doses in the Study

The doses or dose ranges used in the study should be given for all treatments and
the basis for choosing them described (e.g., prior experience in humans, animal
data).
9.4.5

Selection and Timing of Dose for Each Patient

Procedures for selecting each patient's dose of test drug/ investigational product
and active control/comparator should be described. These procedures can vary
from simple random assignment to a selected fixed drug/dose regimen, to use of a
specified titration procedure, or to more elaborate response-determined selection
procedures, e.g., where dose is titrated upward at intervals until intolerance or
10

some specified endpoint is achieved. Procedures for back-titration, if any, should


also be described.
The timing (time of day, interval) of dosing and the relation of dosing to meals
should be described and, if timing was not specified, this should be noted.
Any specific instructions to patients about when or how to take the dose(s) should
be described.
9.4.6

Blinding

A description of the specific procedures used to carry out blinding should be


provided (e.g., how bottles were labeled, use of labels that reveal blind-breakage,
sealed code list/envelopes, double dummy techniques), including the circumstances
in which the blind would be broken for an individual or for all patients (e.g., for
serious adverse events), the procedures used to do this, and who had access to
patient codes. If the study allowed for some investigators to remain unblinded
(e.g., to allow them to adjust medication), the means of shielding other
investigators should be explained. Measures taken to ensure that test
drug/investigational product and placebo were indistinguishable and evidence that
they were indistinguishable should be described, as should the appearance, shape,
smell, and taste of the test material. Measures to prevent unblinding by laboratory
measurements, if used, should be described. If there was a data monitoring
committee with access to unblinded data, procedures to ensure maintenance of
overall study blinding should be described. The procedure used to maintain the
blinding when interim analyses were performed should also be explained.
If blinding was considered unnecessary to reduce bias for some or all of the
observations, this should be explained; e.g., use of a random-zero
sphygmomanometer eliminates possible observer bias in reading blood pressure
and Holter tapes are often read by automated systems that are presumably immune
to observer bias. If blinding was considered desirable but not feasible, the reasons
and implications should be discussed. Sometimes blinding is attempted but is
known to be imperfect because of obvious drug effects in at least some patients
(dry mouth, bradycardia, fever, injection site reactions, changes in laboratory data).
Such problems or potential problems should be identified and, if there were any
attempts to assess the magnitude of the problem or manage it (e.g., by having
endpoint measurements carried out by people shielded from information that might
reveal treatment assignment), they should be described.
9.4.7

Prior and Concomitant Therapy

Which drugs or procedures were allowed before and during the study, whether and
11

how their use was recorded, and any other specific rules and procedures related to
permitted or prohibited concomitant therapy should be described. How allowed
concomitant therapy might affect the outcome due either to drug-drug interaction
or to direct effects on the study endpoints should be discussed, and how the
independent effects of concomitant and study therapies could be ascertained
should be explained.
9.4.8

Treatment Compliance

The measures taken to ensure and document treatment compliance should be


described, e.g., drug accountability, diary cards, blood, urine or other body fluid
drug level measurements, or medication event monitoring.
9.5

Efficacy and Safety Variables


9.5.1

Efficacy and Safety Measurements Assessed and Flow Chart

The specific efficacy and safety variables to be assessed and laboratory tests to be
conducted, their schedule (days of study, time of day, relation to meals, and the
timing of critical measures in relation to test drug administration, e.g., just prior to
next dose, 2 hours after dose), the methods for measuring them, and the persons
responsible for the measurements should be described. If there were changes in
personnel carrying out critical measurements, these should be reported.
It is usually helpful to display graphically in a flow chart (see Annex III of the
guideline) the frequency and timing of efficacy and safety measurements; visit
numbers and times should be shown, or, alternatively, times alone can be used
(visit numbers alone are more difficult to interpret). Any specific instructions (e.g.,
guidance or use of a diary) to the patients should also be noted.
Any definitions used to characterize outcome (e.g., criteria for determining
occurrence of acute myocardial infarction, designation of the location of the
infarction, characterization of a stroke as thrombotic or hemorrhagic, distinction
between TIA and stroke, assignment of cause of death) should be explained in full.
Any techniques used to standardize or compare results of laboratory tests or other
clinical measurements (e.g., ECG, chest X-ray) should also be described. This is
particularly important in multicenter studies.
If anyone other than the investigator was responsible for evaluation of clinical
outcomes (e.g., the sponsor or an external committee to review X-rays or ECG's
or to determine whether the patient had a stroke, acute infarction, or sudden
death), the person or group should be identified. The procedures used, including
means of maintaining blindness and centralizing readings and measurements,
12

should be described fully.


The means of obtaining adverse event data should be described (volunteered,
checklist, or questioning), as should any specific rating scale(s) used and any
specifically planned followup procedures for adverse events or any planned
rechallenge procedure.
Any rating of adverse events by the investigator, sponsor, or external group (e.g.,
rating by severity or likelihood of drug causation) should be described. The criteria
for such ratings, if any, should be given and the parties responsible for the ratings
should be clearly identified. If efficacy or safety was to be assessed in terms of
categorical ratings or numerical scores, the criteria used for point assignment
should be provided (e.g., definitions of point scores). For multicenter studies, how
methods were standardized should be indicated.
9.5.2

Appropriateness of Measurements

If any of the efficacy or safety assessments was not standard, i.e., widely used and
generally recognized as reliable, accurate, and relevant (able to discriminate
between effective and ineffective agents), its reliability, accuracy, and relevance
should be documented. It may be helpful to describe alternatives considered but
rejected.
If a surrogate endpoint (a laboratory measurement or physical measurement or sign
that is not a direct measure of clinical benefit) was used as a study endpoint, this
should be justified, e.g., by reference to clinical data, publications, guidelines, or
previous actions by regulatory authorities.
9.5.3

Primary Efficacy Variable(s)

The primary measurements and endpoints used to determine efficacy should be


clearly specified. Although the critical efficacy measurements may seem obvious,
when there are multiple variables or when variables are measured repeatedly, the
protocol should identify the primary ones with an explanation of why they were
chosen, or designate the pattern of significant findings or other method of
combining information that would be interpreted as supporting efficacy.
If the protocol did not identify the primary variables, the study report should
explain how these critical variables were selected (e.g., by reference to
publications, guidelines, or previous actions by regulatory authorities) and when
they were identified (i.e., before or after the study was completed and unblinded).
If an efficacy threshold was defined in the protocol, this should be described.

13

9.5.4

Drug Concentration Measurements

Any drug concentrations to be measured and the sample collection times and
periods in relation to the timing of drug administration should be described. Any
relation of drug administration and sampling to ingestion of food, posture, and the
possible effects of concomitant medication/alcohol/ caffeine/nicotine should also be
addressed. The biological sample measured, the handling of samples and the
method of measurement used should be described, referring to published and/or
internal assay validation documentation for methodological details. Where other
factors are believed important in assessing pharmacokinetics (e.g., soluble
circulating receptors, renal or hepatic function), the timing and plans to measure
these factors should also be specified.
9.6

Data Quality Assurance

The quality assurance and quality control systems implemented to assure the quality of the
data should be described in brief. If none were used, this should be stated. Documentation
of inter-laboratory standardization methods and quality assurance procedures, if used,
should be provided under Appendix 16.1.10.
Any steps taken at the investigation site or centrally to ensure the use of standard
terminology and the collection of accurate, consistent, complete, and reliable data, such as
training sessions, monitoring of investigators by sponsor personnel, instruction manuals,
data verification, cross-checking, use of a central laboratory for certain tests, centralized
ECG reading, or data audits, should be described. It should be noted whether investigator
meetings or other steps were taken to prepare investigators and standardize performance.
If the sponsor used an independent internal or external auditing procedure, it should be
mentioned here and described in Appendix 16.1.8; audit certificates, if available, should be
provided in the same appendix.
9.7
Size

Statistical Methods Planned in the Protocol and Determination of Sample


9.7.2

Statistical and Analytical Plans

The statistical analyses planned in the protocol and any changes made before
outcome results were available should be described. In this section, emphasis
should be on which analyses, comparisons, and statistical tests were planned, not
on which ones were actually used. If critical measurements were made more than
once, the particular measurements (e.g., average of several measurements over the
entire study, values at particular times, values only from study completers, or last
on-therapy value) planned as the basis for comparison of test drug/investigational
product and control should be specified. Similarly, if more than one analytical
14

approach is plausible, e.g., changes from baseline response, slope analysis,


life-table analysis, the planned approach should be identified. Also, whether the
primary analysis is to include adjustment for covariates should be specified.
If there were any planned reasons for excluding from analysis patients for whom
data are available, these should be described. If there were any subgroups whose
results were to be examined separately, these should be identified. If categorical
responses (global scales, severity scores, responses of a certain size) were to be
used in analyzing responses, they should be clearly defined.
Planned monitoring of the results of the study should be described. If there was a
data monitoring committee, either within or outside the sponsor's control, its
composition and operating procedures should be described and procedures to
maintain study blinding should be given. The frequency and nature of any planned
interim analysis, any specified circumstances in which the study would be
terminated, and any statistical adjustments to be employed because of interim
analyses should be described.
9.7.2

Determination of Sample Size

The planned sample size and the basis for it, such as statistical considerations or
practical limitations, should be provided. Methods for sample size calculation
should be given together with their derivations or source of reference. Estimates
used in the calculations should be given, and explanations should be provided as to
how they were obtained. For a study intended to show a difference between
treatments, the difference the study is designed to detect should be specified. For a
positive control study intended to show that a new therapy is at least as effective
as the standard therapy, the sample size determination should specify the difference
between treatments that would be considered unacceptably large and, therefore,
the difference the study is designed to be able to exclude.
9.8

Changes in the Conduct of the Study or Planned Analyses

Any change in the conduct of the study or planned analyses (e.g., dropping a treatment
group, changing the entry criteria or drug dosages, adjusting the sample size) instituted
after the start of the study should be described. The time(s) and reason(s) for the
change(s), the procedure used to decide on the change(s), the person(s) or group(s)
responsible for the change(s) and the nature and content of the data available (and to
whom they were available) when the change was made should also be described, whether
the change was documented as a formal protocol amendment or not. Personnel changes
need not be included. Any possible implications of the change(s) for the interpretation of
the study should be discussed briefly in this section and more fully in other appropriate
sections of the report. In every section of the report, a clear distinction between conditions
15

(procedures) planned in the protocol and amendments or additions should be made. In


general, changes in planned analyses made prior to breaking the blind have limited
implications for study interpretation. It is therefore particularly critical that the timing of
changes relative to blind breaking and availability of outcome results be well characterized.
10.

STUDY PATIENTS
10.1

Disposition of Patients

There should be a clear accounting of all patients who entered the study, using figures or
tables in the text of the report. The numbers of patients who were randomized and who
entered and completed each phase of the study (or each week/month of the study) should
be provided, as well as the reasons for all postrandomization discontinuations, grouped by
treatment and by major reason (e.g., lost to followup, adverse event, poor compliance). It
may also be relevant to provide the number of patients screened for inclusion and a
breakdown of the reasons for excluding patients during screening, if this could help clarify
the appropriate patient population for eventual drug use. A flow chart is often helpful (see
Annexes IVa and IVb for examples). Whether patients are followed for the duration of the
study, even if drug is discontinued, should be made clear.
In Appendix 16.2.1, there should also be a listing of all patients discontinued from the
study after enrollment, broken down by center and treatment group, giving a patient
identifier, the specific reason for discontinuation, the treatment (drug and dose),
cumulative dose (where appropriate), and the duration of treatment before
discontinuation. Whether or not the blind for the patient was broken at the time of
discontinuation should be noted. It may also be useful to include other information, such
as critical demographic data (e.g., age, sex, race), concomitant medication, and the major
response variable(s) at termination. See Annex V for an example of such a listing.
10.2

Protocol Deviations

All important deviations related to study inclusion or exclusion criteria, conduct of the
trial, patient managements or patient assessment should be described.
In the body of the text, protocol deviations should be appropriately summarized by center
and grouped into different categories, such as:
Those who entered the study even though they did not satisfy the entry criteria.
Those who developed withdrawal criteria during the study but were not
withdrawn.
Those who received the wrong treatment or incorrect dose.
16

Those who received an excluded concomitant treatment.


In Appendix 16.2.2, individual patients with these protocol deviations should be listed,
broken down by center for multicenter studies.
11.

EFFICACY EVALUATION
11.1

Data Sets Analyzed

Exactly which patients were included in each efficacy analysis should be precisely defined,
e.g., all patients receiving any test drugs/investigational products, all patients with any
efficacy observation or with a certain minimum number of observations, only patients
completing the trial, all patients with an observation during a particular time window, or
only patients with a specified degree of compliance. It should be clear, if not defined in the
study protocol, when (relative to study unblinding) and how inclusion/exclusion criteria
for the data sets analyzed were developed. Generally, even if the applicant's proposed
primary analysis is based on a reduced subset of the patients with data, there should also
be, for any trial intended to establish efficacy, an additional analysis using all randomized
(or otherwise entered) patients with any on-treatment data.
There should be a tabular listing of all patients, visits, and observations excluded from the
efficacy analysis provided in Appendix 16.2.3 (see Annex VI for an example). The reasons
for exclusions should also be analyzed for the whole treatment group over time (see
Annex VII for an example).
11.2

Demographic and Other Baseline Characteristics

Group data for the critical demographic and baseline characteristics of the patients, as well
as other factors arising during the study that could affect response, should be presented in
this section and comparability of the treatment groups for all relevant characteristics
should be displayed by use of tables or graphs in section 14.1. The data for the patient
sample included in the all patients with data analysis should be given first. This may be
followed by data on other groups used in principal analyses, such as the per-protocol
analysis or other analyses, e.g., groups defined by compliance, concomitant
disease/therapy, or demographic/baseline characteristics. When such groups are used, data
for the complementary excluded group should also be shown. In a multicenter study,
where appropriate, comparability should be assessed by center, and centers should be
compared.
A diagram showing the relationship between the entire sample and any other analysis
groups should be provided.
The critical variables will depend on the specific nature of the disease and on the protocol
17

but will usually include:


Demographic variables:
- Age
- Sex
- Race
Disease factors:
- Specific entry criteria (if not uniform), duration, stage and severity of disease,
and other clinical classifications and subgroupings in common usage or of known
prognostic significance.
- Baseline values for critical clinical measurements carried out during the study or
identified as important indicators of prognosis or response to therapy.
- Concomitant illness at trial initiation, such as renal disease, diabetes, heart failure.
- Relevant previous illness.
- Relevant previous treatment for illness treated in the study.
- Concomitant treatment maintained, even if the dose was changed during the
study, including oral contraceptive and hormone replacement therapy; treatments
stopped at entry into the study period (or changed at study initiation).
Other factors that might affect response to therapy (e.g., weight, renin status,
antibody levels, metabolic status).
Other possibly relevant variables (e.g., smoking, alcohol intake, special diets) and,
for women, menstrual status and date of last menstrual period, if pertinent for the
study.
In addition to tables and graphs giving group data for these baseline variables, relevant
individual patient demographic and baseline data, including laboratory values, and all
concomitant medication for all individual patients randomized (broken down by treatment
and by center for multicenter studies) should be presented in by-patient tabular listings in
Appendix 16.2.4. Although some regulatory authorities will require all baseline data to be
presented elsewhere in tabular listings, the Appendix to the study report should be limited
to only the most relevant data, generally the variables listed above.
11.3.

Measurements of Treatment Compliance

Any measurements of compliance of individual patients with the treatment regimen under
study and drug concentrations in body fluids should be summarized, analyzed by treatment
group and time interval, and tabulated in Appendix 16.2.5.
11.4

Efficacy Results and Tabulations of Individual Patient Data

18

11.4.1 Analysis of Efficacy


Treatment groups should be compared for all critical measures of efficacy (primary
and secondary endpoints; any pharmacodynamic endpoints studied), as well as
benefit/risk assessment(s) in each patient where these are utilized. In general, the
results of all analyses contemplated in the protocol and an analysis including all
patients with on-study data should be performed in studies intended to establish
efficacy. The analysis should show the size (point estimate) of the difference
between the treatments, the associated confidence interval, and, where utilized, the
results of hypothesis testing.
Analyses based on continuous variables (e.g., mean blood pressure or depression
scale score) and categorical responses (e.g., cure of an infection) can be equally
valid; ordinarily both should be presented if both were planned and are available. If
categories are newly created (i.e., not in the statistical plan) the basis for them
should be explained. Even if one variable receives primary attention (e.g., in a
blood pressure study, supine blood pressure at week x), other reasonable
measures (e.g., standing blood pressure and blood pressures at other particular
times) should be assessed, at least briefly. In addition, the time course of response
should be described, if possible. For a multicenter study, where appropriate, data
display and analysis of individual centers should be included for critical variables to
give a clear picture of the results at each site, especially the larger sites.
If any critical measurements or assessments of efficacy or safety outcomes were
made by more than one party (e.g., both the investigator and an expert committee
may offer an opinion on whether a patient had an acute infarction), overall
differences between the ratings should be shown, and each patient having disparate
assessments should be identified. The assessments used should be clear in all
analyses.
In many cases, efficacy and safety endpoints are difficult to distinguish (e.g., deaths
in a fatal disease study). Many of the principles addressed below should be adopted
for critical safety measures as well.
11.4.2 Statistical/Analytical Issues
The statistical analysis used should be described for clinical and statistical
reviewers in the text of the report, with detailed documentation of statistical
methods (see Annex IX) presented in Appendix 16.1.9. Important features of the
analysis, including the particular methods used, adjustments made for demographic
or baseline measurements or concomitant therapy, handling of dropouts and
missing data, adjustments for multiple comparisons, special analyses of multicenter
studies, and adjustments for interim analyses, should be discussed. Any changes in
19

the analysis made after blind-breaking should be identified.


In addition to the general discussion, the following specific issues should be
addressed (unless not applicable):
11.4.2.1

Adjustments for Covariates

Selection of, and adjustments for, demographic or baseline measurements,


concomitant therapy, or any other covariates or prognostic factors should
be explained in the report, and methods of adjustment, results of analyses,
and supportive information (e.g., ANCOVA or Cox regression output)
should be included in the detailed documentation of statistical methods. If
the covariates or methods used in these analyses differed from those
planned in the protocol, the differences should be explained and, where
possible and relevant, the results of planned analyses should also be
presented. Although not part of the individual study report, comparisons of
covariate adjustments and prognostic factors across individual studies may
be an informative analysis in a summary of clinical efficacy data.

11.4.2.2

Handling of Dropouts or Missing Data

There are several factors that may affect dropout rates. These include the
duration of the study, the nature of the disease, the efficacy and toxicity of
the drug under study, and other factors that are not therapy-related.
Ignoring the patients who dropped out of the study and drawing
conclusions based only on patients who completed the study can be
misleading. A large number of dropouts, however, even if included in an
analysis, may introduce bias, particularly if there are more early dropouts in
one treatment group or the reasons for dropping out are treatment or
outcome related. Although the effects of early dropouts, and sometimes
even the direction of bias, can be difficult to determine, possible effects
should be explored as fully as possible. It may be helpful to examine the
observed cases at various times or, if dropouts were very frequent, to
concentrate on analyses at times when most of the patients were still under
observation and when the full effect of the drug was realized. It may also
be helpful to examine modeling approaches to the evaluation of such
incomplete data sets.
The results of a clinical trial should be assessed not only for the subset of
patients who completed the study, but also for the entire patient population
as randomized or at least for all those with any on-study measurements.
20

Several factors should be considered and compared for the treatment


groups in analyzing the effects of dropouts: The reasons for the dropouts,
the time to dropout, and the proportion of dropouts among treatment
groups at various time points.
Procedures for dealing with missing data, e.g., use of estimated or derived
data, should be described. Detailed explanation should be provided as to
how such estimations or derivations were done and what underlying
assumptions were made.
11.4.2.3

Interim Analyses and Data Monitoring

The process of examining and analyzing data accumulating in a clinical


trial, either formally or informally, can introduce bias and/or increase type I
error. Therefore, all interim analyses, formal or informal, preplanned or ad
hoc, by any study participant, sponsor staff member, or data monitoring
group should be described in full, even if the treatment groups were not
identified. The need for statistical adjustment because of such analyses
should be addressed. Any operating instructions or procedures used for
such analyses should be described. The minutes of meetings of any data
monitoring group and any data reports reviewed at those meetings,
particularly a meeting that led to a change in the protocol or early
termination of the study, may be helpful and should be provided in
Appendix 16.1.9. Data monitoring without code-breaking should also be
described, even if this kind of monitoring is considered to cause no increase
in type I error.
11.4.2.4

Multicenter Studies

A multicenter study is a single study under a common protocol, involving


several centers (e.g., clinics, practices, hospitals) where the data collected
are intended to be analyzed as a whole (as opposed to a post-hoc decision
to combine data or results from separate studies). Individual center results
should be presented, however, where appropriate, e.g., when the centers
have sufficient numbers of patients to make such analysis potentially
valuable, the possibility of qualitative or quantitative treatment-by-center
interaction should be explored. Any extreme or opposite results among
centers should be noted and discussed, considering such possibilities as
differences in study conduct, patient characteristics, or clinical settings.
Treatment comparison should include analyses that allow for center
differences with respect to response. If appropriate, demographic, baseline,
and postbaseline data, as well as efficacy data, should be presented by
center, even though the combined analysis is the primary one.
21

11.4.2.5

Multiple Comparisons/Multiplicity

False/positive findings increase in number as the number of significance


tests (number of comparisons) performed increases. If there was more than
one primary endpoint (outcome variable) or more than one analysis of
particular endpoint, or if there were multiple treatment groups or subsets of
the patient population being examined, the statistical analysis should reflect
awareness of this and either explain the statistical adjustment used for type
I error criteria or give reasons why it was considered unnecessary.
11.4.2.6

Use of an Efficacy Subset of Patients

Particular attention should be devoted to the effects of dropping patients


with available data from analyses because of poor compliance, missed
visits, ineligibility, or any other reason. As noted above, an analysis using
all available data should be carried out for all studies intended to establish
efficacy, even if it is not the analysis proposed as the primary analysis by
the applicant. In general, it is advantageous to demonstrate robustness of
the principal trial conclusions with respect to alternative choices of patient
populations for analysis. Any substantial differences resulting from the
choice of patient population for analysis should be the subject of explicit
discussion.
11.4.2.7

Active-Control Studies Intended to Show Equivalence

If an active control study is intended to show equivalence (i.e., lack of a


difference greater than a specified size) between the test
drug/investigational product and the active control/comparator, the analysis
should show the confidence interval for the comparison between the two
agents for critical endpoints and the relation of that interval to the
prespecified degree of inferiority that would be considered unacceptable.
(See section 9.2 for important considerations when using the active control
equivalence design.)
11.4.2.8

Examination of Subgroups

If the size of the study permits, important demographic or baseline


value-defined subgroups should be examined for unusually large or small
responses and the results presented, e.g., comparison of effects by age, sex,
or race; by severity or prognostic groups; and by history of prior treatment
with a drug of the same class. If these analyses were not carried out
because the study was too small, it should be noted. These analyses are not
intended to salvage an otherwise nonsupportive study but may suggest
22

hypotheses worth examining in other studies or be helpful in refining


labeling information, patient selection, or dose selection. Where there is a
prior hypothesis of a differential effect in a particular subgroup, this
hypothesis and its assessment should be part of the planned statistical
analysis.
11.4.3 Tabulation of Individual Response Data
In addition to tables and graphs representing group data, individual response data
and other relevant study information should be presented in tables. Some
regulatory authorities may require all individual data in archival case report
tabulations. What needs to be included in the report will vary from study to study
and from one drug class to another, and the applicant must decide, if possible after
consultation with the regulatory authority, what to include in an Appendix to the
study report. The study report should indicate what material is included as an
Appendix, what is in the more extensive archival case report tabulations, if
required by the regulatory authority, and what is available on request.
For a controlled study in which critical efficacy measurements or assessments (e.g.,
blood or urine cultures, pulmonary function tests, angina frequency, or global
evaluations) are repeated at intervals, the data listings accompanying the report
should include, for each patient, a patient identifier, all measured or observed
values of critical measurements, including baseline measurements, with notation of
the time during the study (e.g., days on therapy and time of day, if relevant) when
the measurements were made, the drug/dose at the time (if useful, given as
milligram per kilogram (mg/kg)), any measurements of compliance, and any
concomitant medications at the time of, or close to the time of, measurement or
assessment. If, aside from repeated assessments, the study included some overall
responder versus nonresponder evaluation(s) (bacteriologic cure or failure), it
should also be included. In addition to critical measurements, the tabulation should
note whether the patient was included in the efficacy evaluation (and which
evaluation, if more than one), provide patient compliance information, if collected,
and a reference to the location of the case report form, if included. Critical baseline
information such as age, sex, and weight; disease being treated (if more than one in
study); and disease stage or severity is also helpful. The baseline values for critical
measurements would ordinarily be included as zero time values for each efficacy
measurement.
The tabulation described should usually be included in Appendix 16.2.6 of the
study report, rather than in the more extensive case report tabulations required by
some regulatory authorities, because it represents the basic efficacy data
supporting summary tables. Such a thorough tabulation can be unwieldy for review
purposes, however, and it is expected that more targeted displays will be
23

developed as well. For example, if there are many measurements reported,


tabulations of the most critical measurements for each patient (e.g., the blood
pressure value at certain visits might be more important than others) will be useful
in providing an overview of each individual's results in a study, with each patient's
response summarized on a single line or small number of lines.
11.4.4 Drug Dose, Drug Concentration, and Relationships to Response
When the dose in each patient can vary, the actual doses received by patients
should be shown and individual patient's doses should be tabulated. Although
studies not designed as dose-response studies may have limited ability to
contribute dose-response information, the available data should be examined for
whatever information they can yield. In examining the dose response, it may be
helpful to calculate dose as mg/kg body weight or milligram per square meter
(mg/m2) body surface.
Drug concentration information, if available, should also be tabulated (Appendix
16.2.5), analyzed in pharmacokinetic terms, and, if possible, related to response.
Further guidance on the design and analysis of studies exploring dose-response or
concentration response can be found in the ICH Guideline entitled
Dose-Response Information to Support Drug Registration.
11.4.5 Drug-Drug and Drug-Disease Interactions
Any apparent relationship between response and concomitant therapy and between
response and past and/or concurrent illness should be described.
11.4.6 By-Patient Displays
While individual patient data ordinarily can be displayed in tabular listings, it has
on occasion been helpful to construct individual patient profiles in other formats,
such as graphic displays. These might, for example, show the value of a particular
parameter(s) over time, the drug dose over the same period, and the times of
particular events (e.g., an adverse event or change in concomitant therapy). Where
group mean data represent the principal analyses, this kind of case report extract
may offer little advantage; it may be helpful, however, if overall evaluation of
individual responses is a critical part of the analysis.
11.4.7 Efficacy Conclusions
The important conclusions concerning efficacy should be concisely described,
considering primary and secondary endpoints, prespecified and alternative
24

statistical approaches, and results of exploratory analyses.


12.

SAFETY EVALUATION

Analysis of safety-related data can be considered at three levels. First, the extent of exposure
(dose, duration, number of patients) should be examined to determine the degree to which safety
can be assessed from the study. Second, the more common adverse events and laboratory test
changes should be identified, classified in some reasonable way, compared for treatment groups,
and analyzed, as appropriate, for factors that may affect the frequency of adverse reactions/events,
such as time dependence, relation to demographic characteristics, relation to dose or drug
concentration. Finally, serious adverse events and other significant adverse events should be
identified, usually by close examination of patients who left the study prematurely because of an
adverse event, whether or not identified as drug related, or who died.
The ICH Guideline entitled Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting defines serious adverse events as follows: A serious adverse event
(experience) or reaction is any untoward medical occurrence that at any dose: results in death, is
life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization,
results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
For the purpose of this guideline, other significant adverse events are marked hematological and
other laboratory abnormalities and any adverse events that led to an intervention, including
withdrawal of drug treatment, dose reduction, or significant additional concomitant therapy.
In the following sections, three kinds of analysis and display are called for:
1.
Summarized data, often using tables and graphical presentations presented in the main
body of the report;
2.
Listings of individual patient data; and
3.
Narrative statements of events of particular interest.
In all tabulations and analyses, events associated with both test drug and control treatment should
be displayed.
12.1

Extent of Exposure

The extent of exposure to test drugs/investigational products (and to active control and
placebo) should be characterized according to the number of patients exposed, the
duration of exposure, and the dose to which they were exposed.
Duration: Duration of exposure to any dose can be expressed as a median or
mean, but it is also helpful to describe the number of patients exposed for specified
periods of time, such as for 1 day or less, 2 days to 1 week, more than 1 week to 1
25

month, more than 1 month to 6 months. The numbers exposed to test


drug(s)/investigational product(s) for the various durations should also be broken
down into age, sex, and racial subgroups, and any other pertinent subgroups, such
as groups defined by disease (if more than one is represented), disease severity, or
concurrent illness.
Dose: The mean or median dose used and the number of patients exposed to
specified daily dose levels should be given; the daily dose levels used could be the
maximum dose for each patient, the dose with longest exposure for each patient,
or the mean daily dose. It is often useful to provide combined dose-duration
information, such as the numbers exposed for a given duration (e.g., at least 1
month) to the most common dose, the highest dose, or the maximum
recommended dose. In some cases, cumulative dose might be pertinent. Dosage
may be given as the actual daily dose or on a mg/kg or mg/m<SUP>2 basis, as
appropriate. The number of patients exposed to various doses should be broken
down into age, sex, racial, and any other pertinent subgroups.
Drug concentration: If available, drug concentration data (e.g., concentration at
the time of an event, maximum plasma concentration, area under curve) may be
helpful in individual patients for correlation with adverse events or changes in
laboratory variables. (Appendix 16.2.5.)
It is assumed that all patients entered into treatment who received at least one dose of the
treatment are included in the safety analysis; if not, an explanation should be provided.
12.2

Adverse Events
12.2.1 Brief Summary of Adverse Events
The overall adverse event experience in the study should be described in a brief
narrative, supported by the following more detailed tabulations and analyses. In
these tabulations and analyses, events associated with both the test drug and
control treatment should be displayed.
12.2.2 Display of Adverse Events
All adverse events occurring after initiation of study treatments (including events
likely to be related to the underlying disease or likely to represent concomitant
illness, unless there is a prior agreement with the regulatory authority to consider
specified events as disease related) should be displayed in summary tables (section
14.3.1). The tables should include changes in vital signs and any laboratory
changes that were considered serious adverse events or other significant adverse
events.
26

In most cases, it will also be useful to identify in such tables treatment emergent
signs and symptoms (TESS: events not seen at baseline and events that worsened
even if present at baseline).
The tables should list each adverse event, the number of patients in each treatment
group in whom the event occurred, and the rate of occurrence. When treatments
are cyclical, e.g., cancer chemotherapy, it may also be helpful to list results
separately for each cycle. Adverse events should be grouped by body system. Each
event may then be divided into defined severity categories (e.g., mild, moderate,
severe) if these were used. The tables may also divide the adverse events into those
considered at least possibly related to drug use and those considered not related,
or use another causality scheme (e.g., unrelated or possibly, probably, or definitely
related). Even when such a causality assessment is used, the tables should include
all adverse events, whether or not considered drug related, including events
thought to represent intercurrent illnesses. Subsequent analyses of the study or of
the overall safety data base may help to distinguish between adverse events that
are, or are not, considered drug related. So that it is possible to analyze and
evaluate the data in these tables, it is important to identify each patient having each
adverse event. An example of such a tabular presentation is shown below.
ADVERSE EVENTS: NUMBER OBSERVED AND RATE,
WITH PATIENT IDENTIFICATION
Treatment Group X
Mild
Related 1

N=50
Moderate

NR 1

Related

NR

Severe
Related

Total

Total

NR

Related

NR

12(24%)

4(8%)

Body
System A
Event 1

6(12%)

2(4%)

3(6%)

1(2%)

3(6%)

1(2%)

N11 2

N21

N31

N41

N51

N61

N12

N22

N32

N52

N33

N53

N13
N14
N15
N16
Event 2

27

R+NR

NR = not related; related coud be expanded, e.g., as definite, probable, possible.


Patient identification number.

1
2

In addition to these complete tables provided in section 14.3.1, an additional


summary table comparing treatment and control groups, without the patient
identifying numbers and limited to relatively common adverse events (e.g., those in
at least 1 percent of the treated group), should be provided in the body of the
report.
In presenting adverse events, it is important both to display the original terms used
by the investigator and to attempt to group related events (i.e., events that
probably represent the same phenomenon), so that the true occurrence rate is not
obscured. One way to do this is with a standard adverse reaction/events dictionary.
12.2.3 Analysis of Adverse Events
The basic display of adverse event rates described in section 12.2.2 (and located in
section 14.3.1) of the report should be used to compare rates in treatment and
control groups. For this analysis, it may be helpful to combine the event severity
categories and the causality categories, leading to a simpler side-by-side
comparison of treatment groups. In addition, although this is usually best done in
an integrated analysis of safety, if study size and design permit, it may be useful to
examine the more common adverse events that seem to be drug related for
relationship to dosage and mg/kg or mg/m<SUP>2 dose; dose regimen; duration
of treatment; total dose; demographic characteristics such as age, sex, race; other
baseline features such as renal status, efficacy outcomes, and drug concentration. It
may also be useful to examine time of onset and duration of adverse events. A
variety of additional analyses may be suggested by the study results or by the
pharmacology of the test drug/investigational product.
It is not intended that every adverse event be subjected to rigorous statistical
evaluation. It may be apparent from initial display and inspection of the data that a
significant relation to demographic or other baseline features is not present. If the
studies are small and if the number of events is relatively small, it may be sufficient
to limit analyses to a comparison of treatment and control.
Under certain circumstances, life table or similar analyses may be more informative
than reporting of crude adverse event rates. When treatments are cyclical, e.g.,
cancer chemotherapy, it may also be helpful to analyze results separately for each
cycle.
12.2.4 Listing of Adverse Events by Patient
All adverse events for each patient, including the same event on several occasions,
28

should be listed in Appendix 16.2.7, giving both preferred term and the original
term used by the investigator. The listing should be by investigator and by
treatment group and should include:
Patient identifier.
Age, race, sex, weight (height, if relevant).
Location of case report forms, if provided.
The adverse event (preferred term, reported term).
Duration of the adverse event.
Severity (e.g., mild, moderate, severe).
Seriousness (serious/nonserious).
Action taken (none, dose reduced, treatment stopped, specific treatment
instituted, and so forth).
Outcome (e.g., CIOMS format).
Causality assessment (e.g., related/not related). How this was determined
should be described in the table or elsewhere.
Date of onset or date of clinic visit at which the event was discovered.
Timing of onset of the adverse event in relation to the last dose of the test
drug/investigational product (when applicable).
Study treatment at the time of event or the most recent study treatment
taken.
Test drug/investigational product dose in absolute amount, mg/kg or
mg/m<SUP>2, at time of event.
Drug concentration (if known).
Duration of test drug/investigational product treatment.
Concomitant treatment during study.

29

Any abbreviations and codes should be clearly explained at the beginning of the
listing or, preferably, on each page.
12.3.

Deaths, Other Serious Adverse Events, and Other Significant Adverse Events

Deaths, other serious adverse events, and other significant adverse events deserve special
attention.
12.3.1 Listing of Deaths, Other Serious Adverse Events, and Other Significant
Adverse Events
Listings, containing the same information as called for in section 12.2.4, should be
provided for the following events.
12.3.1.1

Deaths

All deaths during the study, including the post-treatment followup period,
and deaths that resulted from a process that began during the study, should
be listed by patient in section 14.3.2.
12.3.1.2

Other Serious Adverse Events

All serious adverse events (other than death but including the serious
adverse events temporally associated with or preceding the deaths) should
be listed in section 14.3.2. The listing should include laboratory
abnormalities, abnormal vital signs, and abnormal physical observations
that were considered serious adverse events.
12.3.1.3

Other Significant Adverse Events

Marked hematological and other laboratory abnormalities (other than those


meeting the definition of serious) and any events that led to an intervention,
including withdrawal of test drug/investigational product treatment, dose
reduction, or significant additional concomitant therapy, other than those
reported as serious adverse events, should be listed in section 14.3.2.
12.3.2 Narratives of Deaths, Other Serious Adverse Events, and Certain Other
Significant Adverse Events
There should be a brief narrative describing each death, other serious adverse
event, and other significant adverse event that is judged to be of special interest
because of clinical importance. These narratives can be placed either in the text of
the report or in section 14.3.3, depending on their number. Events that were
30

clearly unrelated to the test drug/investigational product may be omitted or


described very briefly. In general, the narrative should describe the following: The
nature and intensity of event; the clinical course leading up to event, with an
indication of timing relevant to test drug/investigational product administration;
relevant laboratory measurements; whether the drug was stopped, and when;
countermeasures; post-mortem findings; investigator's opinion on causality and
sponsor's opinion on causality, if appropriate.
In addition, the following information should be included:
Patient identifier.
Age and sex of patient; general clinical condition of patient, if appropriate.
Disease being treated (this is not required if it is the same for all patients)
with duration (of current episode) of illness.
Relevant concomitant/previous illnesses with details of occurrence/
duration.
Relevant concomitant/previous medication with details of dosage.
Test drug/investigational product administered; drug dose, if this varied
among patients; and length of time administered.
12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse Events, and
Other Significant Adverse Events
The significance of the deaths, other serious adverse events, and other significant
adverse events leading to withdrawal, dose reduction, or institution of concomitant
therapy should be assessed with respect to the safety of the test
drug/investigational product. Particular attention should be paid to whether any of
these events may represent a previously unsuspected important adverse effect of
the test drug/investigational product. For serious adverse events that appear of
particular importance, it maybe useful to use life table or similar analyses to show
their relation to time on test drug/investigational product and to assess their risk
over time.
12.4

Clinical Laboratory Evaluation


12.4.1 Listing of Individual Laboratory Measurements by Patient (Appendix
16.2.8) and Each Abnormal Laboratory Value (see section 14.3.4)

31

When required by regulatory authorities, the results of all safety-related laboratory


tests should be available in tabular listings, using a display similar to the following,
where each row represents a patient visit at which a laboratory study was done,
with patients grouped by investigator (if more than one) and treatment group, and
columns include critical demographic data, drug dose data, and the results of the
laboratory tests. Because not all tests can be displayed in a single table, they should
be grouped logically (e.g., hematological tests, liver chemistries, electrolytes,
urinalysis). Abnormal values should be identified, e.g., by underlining or
bracketing. These listings should be submitted as part of the registration/marketing
application, when this is required, or may be available on request.
List of Laboratory Measurement
Laboratory Tests
Patient

Time

Age

#1

T0

70

#2

Weight

Dose

SGOT

SGPT

AP

70 kg

400 mg

V1

V5

V9

T1

V2

V6

V10

T2

V3

V7

V11

T3

V4

V8

V12

V13

V16

V19

T21

V14

V17

V20

T32

V15

V18

V21

T10

65

Sex

Race

50 kg

300 mg

Vn = value of particular test

For all regulatory authorities, there should be a by-patient listing of all abnormal
laboratory values in section 14.3.4, using the format described above. For
laboratory abnormalities of special interest (abnormal laboratory values of potential
clinical importance), it may also be useful to provide additional data, such as
normal values before and after the abnormal value, and values of related laboratory
tests. In some cases, it may be desirable to exclude certain abnormal values from
further analysis. For example, single, nonreplicated, small abnormalities of some
tests (e.g., uric acid or electrolytes) or occasional low values of some tests (e.g.,
transaminase, alkaline phosphatase, or BUN) can probably be defined as clinically
insignificant and excluded. Any such decisions should be clearly explained,
however, and the complete list of values provided (or available to authorities on
request) should identify every abnormal value.
12.4.2 Evaluation of Each Laboratory Parameter
32

The necessary evaluation of laboratory values will in part be determined by the


results seen, but, in general, the following analyses should be provided. For each
analysis, comparison of the treatment and control groups should be carried out, as
appropriate and compatible with study size. In addition, normal laboratory ranges
should be given for each analysis.
12.4.2.1

Laboratory Values Over Time

For each parameter at each time over the course of the study (e.g., at each
visit) the following should be described: The group mean or median values,
the range of values, and the number of patients with abnormal values or
with abnormal values that are of a certain size (e.g., twice the upper limit of
normal or five times the upper limit; choices should be explained). Graphs
may be used.
12.4.2.2

Individual Patient Changes

An analysis of individual patient changes by treatment group should be


given. A variety of approaches may be used, including:
i)
Shift tables - These tables show the number of patients
who are low, normal, or high at baseline and at selected time
intervals.
ii)
Tables showing the number or fraction of patients who had
a change in parameter of a predetermined size at selected time
intervals. For example, for BUN, it might be decided that a change
of more than 10 mg/dL BUN should be noted. For this parameter,
the number of patients having a smaller or greater change would be
shown for one or more visits, usually grouping patients separately
depending on baseline BUN (normal or elevated). The possible
advantage of this display, compared to the usual shift table, is that
changes of a certain size are noted, even if the final value is not
abnormal.
iii)
A graph comparing the initial value and the on-treatment
values of a laboratory measurement for each patient by locating the
point defined by the initial value on the abscissa and a subsequent
value on the ordinate. If no changes occur, the point representing
each patient will be located on the 45 deg. line. A general shift to
higher values will show a clustering of points above the 45 deg.
line. As this display usually shows only a single time point for a
single treatment, interpretation requires a time series of these plots
33

for treatment and control groups. Alternatively, the display could


show baseline and most extreme on-treatment value. These displays
identify outliersreadily (it is useful to include patient identifiers for
the outliers).
12.4.2.3.

Individual Clinically Significant Abnormalities

Clinically significant changes (defined by the applicant) should be


discussed. A narrative of each patient whose laboratory abnormality was
considered a serious adverse event and, in certain cases, considered an
other significant adverse event, should be provided under section 12.3.2
or 14.3.3. When toxicity grading scales are used (e.g., WHO, NCI),
changes graded as severe should be discussed regardless of seriousness. An
analysis of the clinically significant changes, together with a recapitulation
of discontinuations due to laboratory measurements, should be provided
for each parameter. The significance of the changes and likely relation to
the treatment should be assessed, e.g., by analysis of such features as
relationship to dose, relationship to drug concentration, disappearance on
continued therapy, positive dechallenge, positive rechallenge, and the
nature of concomitant therapy.
12.5.

Vital Signs, Physical Findings, and Other Observations Related to Safety

Vital signs, other physical findings, and other observations related to safety should be
analyzed and presented in a way similar to laboratory variables. If there is evidence of a
drug effect, any dose-response or drug-concentration-response relationship or relationship
to patient variables (e.g., disease, demographics, concomitant therapy) should be identified
and the clinical relevance of the observation described. Particular attention should be given
to changes not evaluated as efficacy variables and to those considered to be adverse
events.
12.6

Safety Conclusions

The overall safety evaluation of the test drug(s)/investigational product(s) should be


reviewed, with particular attention to events resulting in changes of dose or need for
concomitant medication, serious adverse events, events resulting in withdrawal, and
deaths. Any patients or patient groups at increased risk should be identified and particular
attention should be paid to potentially vulnerable patients who may be present in small
numbers, e.g., children, pregnant women, frail elderly, people with marked abnormalities
of drug metabolism or excretion. The implication of the safety evaluation for the possible
uses of the drug should be described.
13.

DISCUSSION AND OVERALL CONCLUSIONS


34

The efficacy and safety results of the study and the relationship of risks and benefits should be
briefly summarized and discussed, referring to the tables, figures, and sections above as needed.
The presentation should not simply repeat the description of results nor introduce new results.
The discussion and conclusions should clearly identify any new or unexpected findings, comment
on their significance, and discuss any potential problems such as inconsistencies between related
measures. The clinical relevance and importance of the results should also be discussed in the light
of other existing data. Any specific benefits or special precautions required for individual subjects
or at-risk groups and any implications for the conduct of future studies should be identified.
Alternatively, such discussions may be reserved for summaries of safety and efficacy referring to
the entire dossier (integrated summaries).
14.
TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN
THE TEXT
Figures should be used to visually summarize the important results, or to clarify results that are
not easily understood from tables.
Important demographic, efficacy, and safety data should be presented in summary figures or tables
in the text of the report. However, if these become obtrusive because of size or number they
should be presented here, cross-referenced to the text, along with supportive, or additional,
figures, tables, or listings.
The following information may be presented in this section of the core clinical study report:
14.1

Demographic Data Summary figures and tables.

14.2

Efficacy Data Summary figures and tables.

14.3

Safety Data Summary figures and tables.


14.3.1 Displays of Adverse Events
14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse
Events
14.3.4 Abnormal Laboratory Value Listing (each patient)

15.

REFERENCE LIST

A list of articles from the literature pertinent to the evaluation of the study should be provided.
35

Copies of important publications should be attached in an Appendix (Appendices 16.1.11 and


16.1.12). References should be given in accordance with the internationally accepted standards of
the 1979 Vancouver Declaration on Uniform Requirements for Manuscripts Submitted to
Biomedical Journals or the system used in Chemical Abstracts.

16.

APPENDICES

This section should be prefaced by a full list of all Appendices available for the study report.
Where permitted by the regulatory authority, some of the following Appendices need not be
submitted with the report but need to be provided only on request.
The applicant should therefore clearly indicate those Appendices that are submitted with the
report.
N.B.: In order to have Appendices available on request, they should be finalized by the time of
filing of the submission.
16.1

Study Information
16.1.1 Protocol and protocol amendments.
16.1.2 Sample case report form (unique pages only).
16.1.3 List of IEC's or IRB's (plus the name of the committee chair if required by
the regulatory authority) and representative written information for patient and
sample consent forms.
16.1.4 List and description of investigators and other important participants in the
study, including brief (one page) CV's or equivalent summaries of training and
experience relevant to the performance of the clinical study.
16.1.5 Signatures of principal or coordinating investigator(s) or sponsor's
responsible medical officer, depending on the regulatory authority's requirement.
16.1.6 Listing of patients receiving test drug(s)/investigational product(s) from
specific batches, where more than one batch was used.
16.1.7 Randomization scheme and codes (patient identification and treatment
assigned).
16.1.8 Audit certificates (if available).

36

16.1.9 Documentation of statistical methods.


16.1.10
Documentation of inter-laboratory standardization methods and
quality assurance procedures if used.

16.2

16.1.11.

Publications based on the study.

16.1.12

Important publications referenced in the report.

Patient Data Listings


16.2.1 Discontinued patients.
16.2.2 Protocol deviations.
16.2.3 Patients excluded from the efficacy analysis.
16.2.4 Demographic data.
16.2.5 Compliance and/or drug concentration data (if available).
16.2.6 Individual efficacy response data.
16.2.7 Adverse event listings (each patient).
16.2.8 Listing of individual laboratory measurements by patient, when required by
regulatory authorities.

16.3.

Case Report Forms (CRF's)


16.3.1 CRF's for deaths, other serious adverse events, and withdrawals for
adverse events.
16.3.2 Other CRF's submitted.

16.4

Individual Patient Data Listings

37

ANNEX I
SYNOPSIS
Name of Sponsor/Company:

Name of Finished Product:

Individual Study Table


Referring to Part
of the Dossier
Volume:
Page:

Name of Active Ingredient:

Title of Study:

Investigators:

Study centre(s):

Publication (reference)

Studied period (years):


(date of first enrolment)
(date of last completed)

Phase of development:

Objectives:

Methodology:

Number of patients (planned and analyzed):

Diagnosis and main criteria for inclusion:

Test product, dose and mode of administration, batch number:

Duration of treatment:

Reference therapy, dose and mode of administration, batch number

I-1

(For National Authority


Use only)

Name of Sponsor/Company:

Name of Finished Product:

Individual Study Table


Referring to Part
of the Dossier
Volume:
Page:

Name of Active Ingredient:

Criteria for evaluation:


Efficacy:
Safety:

Statistical methods:

SUMMARY - CONCLUSIONS
EFFICACY RESULTS :

SAFETY RESULTS:

CONCLUSION:

Date of the report:

I-2

(For National Authority


Use Only)

ANNEX II

PRINCIPAL OR COORDINATING
INVESTIGATOR(S) SIGNATURE(S)
OR SPONSOR S RESPONSIBLE MEDICAL OFFICER

STUDY TITLE:
STUDY AUTHOR(S):

_______________
..............................................................................
...
..............................................................................
...

I have read this report and confirm that to the best of my knowledge it accurately
describes the conduct and results of the study
INVESTIGATOR:______________________
OR SPONSORS RESPONSIBLE
MEDICAL OFFICER

SIGNATURE(S)____________

AFFILIATION:________________________

______________________
_______________________

DATE:______________________________

II-1

ANNEX IIIa
STUDY DESIGN AND SCHEDULE OF ASSESSMENTS
A

TREATMENT
PERIOD

Run-in

B1

B2

C1

C2

TEST DRUG/
INVESTIGATIONAL
A

PRODUCT

TEST DRUG/
INVESTIGATIONAL
PRODUCT A

5 mg

10 mg

5 mg

TEST DRUG/
INVESTIGATIONAL
B

PRODUCT

TEST DRUG/
INVESTIGATIONAL
PRODUCT B

5 mg

10 mg

5 mg

10 mg

10 mg

Weeks

-2(-3)

12

Visit

x2

x1

Exercise test 24 h
Medical history

Physical examination

ECG

Lab. invest.

Adverse events

1 = 14-20 days after visit 1


2 = 1-7 days after the first exercise test

IIIa-1

ANNEX IIIb

STUDY DESIGN AND SCHEDULE OF ASSESSMENTS

Assessment

Screening

Study Week

-2

Informed
Consent

History

Physical
Exam.

Runin
-1

Baseline
0

Treatment
1

Follow-up
4

Effectiveness
primary
variable

secondary
variable

Adverse
events

Lab. tests

Body weight

Safety

IIIb-1

x
x

N = 59
WITHDRAWN

ADVERSE EVENT (20)


UNSAT. RESPONSE
EFFICACY (1)
FAILURE TO RETURN (6)
OTHER MED. EVENT (5)
OTHER NONMED. EVENT (5)
PROTOCOL VIOLATION (10)
PATENT REQUEST (12)

N = 281
COMPLETED
STUDY

N = 340
REGIMEN A

N=
WITHDRAWN

ADVERSE EVENT (19)


UNSAT. RESPONSE
EFFICACY (2)
FAILURE TO RETURN (8)
OTHER MED. EVENT (8)
OTHER NONMED. EVENT (4)
PROTOCOL VIOLATION (10)
PATENT REQUEST (10)

N=
COMPLETED
STUDY

N=
REGIMEN B

N=
WITHDRAWN

IVa-1

N = 1,361
PATIENTS COMPLETING STUDY

ADVERSE EVENT (26)


UNSAT. RESPONSE
EFFICACY (1)
FAILURE TO RETURN (7)
OTHER MED. EVENT (4)
OTHER NONMED. EVENT (6)
PROTOCOL VIOLATION (3)
PATENT REQUEST (25)

N=
COMPLETED
STUDY

N=
REGIMEN C

N = 1,724
PATIENTS RECEIVING
DOUBLE-BLINDED MEDICATION

Disposition of Patients

N=
WITHDRAWN

ADVERSE EVENT (24)


UNSAT. RESPONSE
EFFICACY (1)
FAILURE TO RETURN (6)
OTHER MED. EVENT (8)
OTHER NONMED. EVENT (7)
PROTOCOL VIOLATION (6)
PATENT REQUEST (27)

N=
COMPLETED
STUDY

N=
REGIMEN D

N=
WITHDRAWN

ADVERSE EVENT (42)


UNSAT. RESPONSE
EFFICACY (0)
FAILURE TO RETURN (6)
OTHER MED. EVENT (14)
OTHER NONMED. EVENT (1)
PROTOCOL VIOLATION (14)
PATENT REQUEST (15)

N=
COMPLETED
STUDY

N=
REGIMEN E

ANNEX IVa

ANNEX IVb

DISPOSITION OF PATIENTS

N = 2670
PATIENTS SCREENED

N = 17320
PATIENTS RANDOMIZED

N =8
DID NOT RECEIVE
ANY MEDICATION
Reasons:
____________ (2)
____________ (4)
____________ (2)

N=
REGIMEN A

N=
COMPLETED

N=
WITHDRAWN

N = 938
Screening Failures
Reasons:
____________ (300)
____________ (271)
____________

N = 1724
PATIENTS RECEIVING
DOUBLE-BLIND
MEDICATION

N=
REGIMEN B

N=
COMPLETED

N=
WITHDRAWN

ADVERSE EVENT (20)


UNSAT. RESPONSE (32)
etc .....
etc. ....

IVb-1

N=
REGIMEN C

N=
COMPLETED

N=
WITHDRAWN

ANNEX V
STUDY #
(Data Set Identification)
LISTING OF PATIENTS WHO DISCONTINUED THERAPY
Centre.:
Treatment

Patient#

Sex

Age

Last Visit

Duration Dose

Concomitant
Medication

Test Drug/
investigational product

Reason for
Discontin.
Adverse
reaction *

Therapy
failure
Treatment

Patient#

Sex

Age

Last Visit

Duration Dose

Concomitant
Medication

Sex

Age

Last Visit

Duration Dose

Concomitant
Medication

Reason for
Discontin.

Reason for
Discontin.

Active Control/
Comparator
Treatment

Patient#

Placebo
*

The specific reaction leading to discontinuation

(Repeat for other centers)

V-1

ANNEX VI

STUDY #
(Data Set Identification)
Listing of Patients and Observations Excluded from Efficacy Analysis
Center.:
Treatment Patient # Sex Age Observation Excluded Reason(s)
Test Drug/Investigational Product
Treatment Patient # Sex Age Observation Excluded Reason(s)
Active Control/Comparator
Treatment Patient # Sex Age Observation Excluded Reason(s)
Placebo
(Repeat for other centres)
Reference Tables
Summary:

VI-1

ANNEX VII
STUDY #
(Data Set Identification)
Number of Patients Excluded from Efficacy Analysis
Test Drug/Investigational Product N =
Reason

___1___

Week
___2___

________
________
________
________
________
________
________

_______
_______
_______
_______
_______
_______
_______

_______
_______
_______
_______
_______
_______
_______

_______
_______
_______
_______
_______
_______
_______

_______
_______
_______
_______
_______
_______
_______

_______

_______

_______

Total

_______

___4___

___8___

Similar tables should be prepared for the other treatment groups.

VII-1

ANNEX VIII
GUIDANCE FOR SECTION 11.4.2 -- STATISTICAL/ANALYTICAL ISSUES
AND APPENDIX 16.1.9
A.

Statistical Considerations

Details of the statistical analysis performed on each primary efficacy variable should be presented
in Appendix 16.1.9. Details reported should include at least the following information:
(a)
The statistical model underlying the analysis. This should be presented precisely
and completely, using references if necessary.
(b)
A statement of the clinical claim tested in precise statistical terms, e.g., in terms of
null and alternative hypotheses.
(c)
The statistical methods applied to estimate effects, construct confidence intervals,
etc. Literature references should be included where appropriate.
(d)
The assumptions underlying the statistical methods. It should be shown, insofar as
statistically reasonable, that the data satisfy crucial assumptions, especially when necessary
to confirm the validity of an inference. When extensive statistical analyses have been
performed by the applicant, it is essential to consider the extent to which the analyses were
planned prior to the availability of data and, if they were not, how bias was avoided in
choosing the particular analysis used as a basis for conclusions. This is particularly
important in the case of any subgroup analyses, because if such analyses are not
preplanned they will ordinarily not provide an adequate basis for definitive conclusions.
(i)
In the event data transformation was performed, a rationale for the choice
of data transformation along with interpretation of the estimates of treatment
effects based on transformed data should be provided.
(ii)
A discussion of the appropriateness of the choice of statistical procedure
and the validity of statistical conclusions will guide the regulatory authority's
statistical reviewer in determining whether reanalysis of data is needed.
(e)
The test statistic, the sampling distribution of the test statistic under the null
hypothesis, the value of the test statistic, significance level (i.e., p-value), and intermediate
summary data, in a format that enables the regulatory authority's statistical reviewer to
verify the results of the analysis quickly and easily. The p-values should be designated as
one or two tailed. The rationale for using a one-tailed test should be provided.

VIII-1

For example, the documentation of a two-sample t-test should consist of the value of the
t-statistic, the associated degrees of freedom, the p-value, the two sample sizes, mean and
variance for each of the samples, and the pooled estimate of variance. The documentation
of multicenter studies analyzed by analysis of variance techniques should include, at a
minimum, an analysis of variance table with terms for centers, treatments, their interaction,
error, and total. For crossover designs, the documentation should include information
regarding sequences, patients within sequences, baselines at the start of each period,
washouts and length of washouts, dropouts during each period, treatments, periods,
treatment by period interaction, error, and total. For each source of variation, aside from
the total, the table should contain the degrees of freedom, the sum of squares, the mean
square, the appropriate F-test, the p-value, and the expected mean square.
Intermediate summary data should display the demographic data and response data,
averaged or otherwise summarized, for each center-by-treatment combination (or other
design characteristic such as sequence) at each observation time.
B.
Format and Specifications for Submission of Data Requested by Regulatory Authority's
Statistical Reviewers
In the report of each controlled clinical study, there should be data listings (tabulations) of patient
data utilized by the sponsor for statistical analyses and tables supporting conclusions and major
findings. These data listings are necessary for the regulatory authority's statistical review, and the
sponsor may be asked to supply these patient data listings in a computer-readable form.

VIII-2

Part 3
Submissions

SECTION 4

Electronic Submission Guidances

PowerPoint presentation on providing regulatory submissions in electronic format


including:
o Overview.
o Available guidances traditional electronic submissions.
o Electronic submissions using eCTD specifications.
o eCTD guidance changes from eNDA guidance-continuation of eNDA
guidance.
o Submissions 101: references.

eCTD Guidance Overview

Gary M Gensinger, MBA


Director, Review Technology Staff
Center for Drug Evaluation and Research

esub@cder.fda.gov

Overview
Available Guidances
Traditional Electronic Submissions
Electronic Submissions using eCTD
Specifications

eCTD Guidance
Changes from eNDA Guidance
Continuation of eNDA Guidance

Submissions 101 References


esub@cder.fda.gov

Electronic Submission Guidances


Traditional Electronic Submission

Providing Regulatory Submissions in


Electronic Format
NDA (Published January, 1999)
Advertising and Promotional Labeling
(Published January 2001)
ANDA (Published June, 2002)
Periodic Safety Report (Published June
2003)
esub@cder.fda.gov

Electronic Submission Guidances


Using eCTD Specifications

Providing Regulatory Submissions in


Electronic Format - Human Pharmaceutical
Product Applications and Related
Submissions
All submission types
NDA, ANDA, BLA, IND, DMF, Annual Reports, Periodic
Safety Reports, Advertising and Promotional Labeling

Published as draft August 28, 2003


Preferred Format for Submissions

esub@cder.fda.gov

Electronic Submissions Using eCTD


Specifications
Guidance Published August, 2003
eCTD Specifications
FDA eCTD Table of Contents Headings and Hierarchy
FDA Module 1 Specification
FDA Modules 2 to 5 Specification
Study Tagging File Specification

Specifications Available On-Line


http://www.fda.gov/cder/regulatory/ersr/default.htm

Current eNDA/eANDA Guidances remain available


as an alternative to the eCTD

esub@cder.fda.gov

eCTD Changes

XML-based eCTD Backbone replaces PDF Tables of Content


Increased document granularity in accordance with ICH eCTD
agreements
No requirement to submit technical sections or study reports in
paper
EVS processor performs rigid validation of backbone against
DTD
Requires strict adherence to specifications
Do not add or modify leafs within the backbone
Once a submission is sent in eCTD format all future
submissions for the application should be in eCTD format
Opportunity to use Part 11 Compliant Electronic Signatures

esub@cder.fda.gov

What doesnt change


Data files submitted in SAS XPORT
format
Documents submitted in PDF Format
Draft labeling submitted in MS Word
Office XP is being deployed

esub@cder.fda.gov

Implementing the Guidance


Initial Pilot Phase
Contact CDER prior to generating pilot submission
Review process and make adjustments

Pilot submission evaluated for technical


compliance only unless directed otherwise
Accepting all submission types, e.g., IND,
NDA, Amendments, Master Files, Annual
Reports

esub@cder.fda.gov

Submissions 101

esub@cder.fda.gov

Just say no
No paper unless required for original
signatures
No Word files or file formats not
specified in the guidance
No electronic submissions or records
sent directly to a reviewer or project
manager
No electronic desk copies
esub@cder.fda.gov

Just dont do it
Dont send electronic submissions to
the division document rooms
Dont use node extensions in preparing
eCTD
Dont combine multiple documents into
single PDF
Dont send customized style sheets
Dont hide your media place it in the
volume with your cover letter.
esub@cder.fda.gov

References
CDER Contact for information on eCTD
submissions
eSub@cder.fda.gov

Electronic Regulatory Submissions and


Review website
http://www.fda.gov/cder/regulatory/ersr/default.htm

International Conference on Harmonization


http://www.ich.org

esub@cder.fda.gov

SECTION 5

Guidance for Industry


Providing Regulatory Submissions
in Electronic Format Using
eCTD Specifications

This is one in a series of guidance documents intended to assist applicants making


regulatory submissions to the FDA in electronic format using the eCTD specifications.
This guidance discusses issues related to the electronic submission of applications for
human pharmaceutical products and related submissions, including abbreviated new
drug applications (ANDAs), biologics license applications (BLAs), investigational new
drug applications (INDs), new drug application (NDAs), master files, advertising
material, and promotional labeling. At this time, this does not include applications
supporting combination products.

Guidance for Industry


Providing Regulatory Submissions in
Electronic Format Human
Pharmaceutical Product Applications
and Related Submissions Using the
eCTD Specifications
Additional copies are available from:
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
and/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
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)
April 2006
Electronic Submissions
Revision 1

Contains Nonbinding Recommendations

I.

TABLE OF CONTENTS
INTRODUCTION............................................................................................................. 1

II.

GENERAL ISSUES .......................................................................................................... 2

A.

Scope ............................................................................................................................................... 2

B.

Guidance on the Content of Applications and Related Submissions ........................................ 2

C.

ICH eCTD Specification................................................................................................................ 3

D.

Document Granularity and Table of Contents Headings........................................................... 3

E.

Electronic Submissions.................................................................................................................. 4

F.

Document Information for Previous Submissions ...................................................................... 4

G.

Referencing Previously Submitted Documents ........................................................................... 5

H.

Refuse to File .................................................................................................................................. 5

I.

Submission of Paper Copies.......................................................................................................... 6

J.

Scanned Documents ....................................................................................................................... 6

K.

The FDA District Office Copy ...................................................................................................... 6

L.

Electronic Signatures..................................................................................................................... 6

M. Number of Copies of Electronic Files........................................................................................... 6


N.

Naming Electronic Files ................................................................................................................ 6

O.

Naming Folders .............................................................................................................................. 7

P.

File Formats.................................................................................................................................... 7

Q.

PDF Bookmarks and Hypertext Links......................................................................................... 8

R.

Sending Electronic Submissions ................................................................................................... 8

S.

Technical Problems or Questions ................................................................................................. 8

III.

ORGANIZING THE MAIN SUBMISSION FOLDER................................................. 8

A.

B.

Module 1 Administrative Information and Prescribing Information Folder........................... 9


1.
2.
3.
4.
5.
6.

eCTD backbone document information files.................................................................................... 9


Cover letter (optional) ..................................................................................................................... 9
Labeling ......................................................................................................................................... 10
Advertisements and promotional material..................................................................................... 10
Marketing annual reports .............................................................................................................. 11
Information amendments ............................................................................................................... 11
Module 2 Summary Folder ......................................................................................................... 11

C.

Module 3 Quality Folder ............................................................................................................. 12

D.

Module 4 Safety Folder ............................................................................................................... 12


1. Study reports .................................................................................................................................. 12
2. Literature references...................................................................................................................... 13
3. Datasets ......................................................................................................................................... 13

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E.

IV.

Module 5 Clinical Study Reports Folder ................................................................................... 13


1.
2.
3.
4.
5.
6.

Tabular listing of all clinical studies ............................................................................................. 14


Study reports .................................................................................................................................. 14
Case report forms .......................................................................................................................... 15
Datasets ......................................................................................................................................... 15
Periodic safety update reports ....................................................................................................... 15
Literature references...................................................................................................................... 16

UTILITY FOLDER ........................................................................................................ 16

A.

Document Type Definition Folder .............................................................................................. 16

B.

Style Folder................................................................................................................................... 16

Technical specifications associated with this guidance will be provided as stand alone documents. They
will be updated periodically. To ensure that you have the most recent versions, check the appropriate
center's guidance Web page. For CBER, this Web site is http://www.fda.gov/cber/esub/esub.htm. For
CDER, this Web site is http://www.fda.gov/cder/regulatory/ersr/ectd.htm.

ii

Contains Nonbinding Recommendations

Guidance for Industry1


Providing Regulatory Submissions in Electronic Format Human
Pharmaceutical Product Applications and Related Submissions
Using the eCTD Specifications

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. 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 guidance documents intended to assist applicants making regulatory
submissions to the FDA in electronic format using the electronic common technical document
(eCTD) specifications. This guidance discusses issues related to the electronic submission of
applications for human pharmaceutical products2 and related submissions, including abbreviated
new drug applications (ANDAs), biologics license applications (BLAs), investigational new drug
applications (INDs), new drug application (NDAs), master files (e.g., drug master files),
advertising material, and promotional labeling.3 At this time, this does not include applications
supporting combination products.
We have revised this guidance, which was first published in October 2005, to correct the names
of the eCTD backbone and U.S. Regional backbone files referenced in section IV.A.
1

This guidance has been developed by the Center for Drug Evaluation and Research (CDER) and the Center for
Biologics Evaluation and Research (CBER).

Human pharmaceutical products include those products that meet the definition of drug under the Food, Drug and
Cosmetic Act, including those that are chemically synthesized and those derived from living sources (biologic
products).
3

Agency guidance documents on electronic submissions will be updated regularly to reflect the evolving nature of
the technology and the experience of those using this technology.
Paperwork Reduction Act of 1995: This guidance contains information collection provisions that are subject to
review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520). The collections of information in this guidance have been approved under OMB Control Nos. 09100014, 0910-0001, and 0910-0338.

Contains Nonbinding Recommendations


The goals of the guidance are to enhance the receipt, processing, and review of electronic
submissions to the FDA. Specifically, this guidance makes recommendations regarding the use
of the eCTD backbone files developed through the International Conference on Harmonisation
(ICH) to facilitate efficient submission handling. In addition, the guidance provides more
specificity than in previous guidances for electronic submissions with regard to the organization
of individual submissions. Finally, the guidance harmonizes the organization and formatting of
electronic submissions for multiple submission types.
This guidance refers to a series of technical specifications associated with the guidance. They
are being provided as stand alone documents to make them more accessible to the user. The
associated specifications will be updated periodically. To ensure that you have the most
recent versions, check the appropriate center's guidance Web page.
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.
II.

GENERAL ISSUES

This portion of the guidance makes recommendations on general organizational issues related to
the electronic submission of applications for human pharmaceutical products using the cCTD
specifications. The requirements for the content of such applications are described in our
regulations in chapter 21 of the Code of Federal Regulations (CFR). Additional
recommendations on the contents of applications are provided in Agency guidances, which are
available on the Agency Web page.
A.

Scope

This guidance applies to marketing applications (ANDAs, BLAs, NDAs), investigational


applications (INDs), and related submissions (master files, advertising material, and promotional
labeling). The guidance applies equally to original submissions, supplements, annual reports, and
amendments to these applications and related submissions, including correspondence. This
guidance does not apply to electronic submission of prelicense or preapproval inspection
materials.
B.

Guidance on the Content of Applications and Related Submissions

This document provides general guidance on how to organize application information for
electronic submission to the Agency using the eCTD specifications. Guidance on the information
to be included in the technical sections of applications and submissions is described in a series of
guidance documents based on the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) common technical

Contains Nonbinding Recommendations


document (CTD): M4: Organization of the CTD, M4Q: The CTD Quality; M4S The CTD
Safety; and M4E: The CTD Efficacy.
C.

ICH eCTD Specification

The recommendations made here on how to organize application information are based on the
ICH CTD and the electronic CTD (eCTD), which was developed by the ICH M2 expert working
group. Although the CTD and the eCTD were designed for marketing applications, they could
apply equally to other submission types, including INDs, master files, advertising material, and
promotional labeling.4 Details on the specification for the ICH eCTD can be found in the
guidance document M2 eCTD: Electronic Common Technical Document Specification.
D.

Document Granularity and Table of Contents Headings

Submissions are a collection of documents. A document is a collection of information that


includes forms, reports, and datasets. When making an electronic submission, each document
should be provided as a separate file.5 The documents, whether for a marketing application, an
investigational application, or a related submission, should be organized based on the five
modules in the CTD: module 1 includes administrative information and prescribing information,
module 2 includes CTD summary documents, module 3 includes information on quality, module
4 includes the nonclinical study reports, and module 5 includes the clinical study reports.
A table of contents is defined by headings arranged in a hierarchical fashion. See the associated
specification, Comprehensive Table of Contents Headings and Hierarchy for the comprehensive
listing of headings and hierarchy Because this is a comprehensive listing, not all headings are
applicable to all submissions or submission types. All of the information you need to submit is
covered by these headings. If you think other headings are needed, you should contact our
electronic submission coordinators prior to using any other headings (see section II.S of this
guidance). Reviewers will not be able to access documents associated with headings not listed
in the Comprehensive Table of Contents Headings and Hierarchy.
Unless otherwise specified, documents should be organized so that the subject matter of the
document is specifically associated with the lowest heading in the table of contents hierarchy.
For example, if you look at the associated document Comprehensive Table of Contents
Headings and Hierarchy, the headings Meeting request and Meeting background material
are the lowest headings in the Meeting hierarchy. Therefore, the meeting request and meeting
background material would be in two separate documents the meeting request in one
document and the meeting background material in another document.
A document can be associated with more than one heading. However, the actual electronic file
would only be provided once. The eCTD specifications provide details on how to refer to an
electronic file.

Advertising and promotional labeling provided with marketing applications.


Some documents are provided in more than one file because a file containing everything would be too large. See
specifications for the size limitations for a file.

Contains Nonbinding Recommendations

E.

Electronic Submissions

Under our regulations (21 CFR 11.2(b)(2)), applicants and sponsors are expected to contact us
for details on how to proceed with electronic submissions. These details are usually provided in
guidance documents. For example, we are already receiving marketing application submissions
for human pharmaceutical products in electronic format based on details provided in the
guidances for industry Providing Regulatory Submissions in Electronic Format NDAs,
Providing Regulatory Submissions in Electronic Format ANDAs, Providing Regulatory
Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format
Biologics Marketing Applications, and Providing Regulatory Submissions in Electronic
Format General Considerations.6 However, we recommend that you begin submitting eCTD
backbone files as described in this guidance because we believe that having the information in
the eCTD backbone files will result in greater efficiency in the future. In time, the other
guidances may be withdrawn because they may no longer be needed.
When we are ready to receive a particular submission type in electronic format only, we usually
identify it in public docket 92S-0251. Under 21 CFR part 11, you then have the option of
providing that submission type in electronic format according to FDA guidance so that the
Agency may adequately process, archive, and review the files.
Once you begin to submit a specific application in electronic format based on this guidance,
subsequent submissions to the application, including amendments and supplements, should
include eCTD backbone files. Without the eCTD backbone files, we will not be able to
adequately manage, process, archive, or review the submissions. If you choose to submit an
original application using the eCTD backbone files, you should obtain an application number in
advance by contacting the appropriate center. You may obtain the number at any time and the
numbers will not be reused.
We believe it is most beneficial to begin your eCTD-based submissions with the initial
submission of an application. Contact the appropriate center first if you wish to make eCTDbased submissions to pending applications. You should avoid the submission of any paper
documents when you follow the recommendations in this document. The maximum benefit will
be derived once an application is in electronic format. This is particularly true for the IND,
where submissions are provided over a long period of time. You should submit the electronic
information for all files in the eCTD backbone files following the specifications associated with
this guidance.
F.

Document Information for Previous Submissions

If you decide to submit a specific application in electronic format based on this guidance, you do
not have to provide eCTD backbone files for the previous submissions to the application. For
example, if you submitted an original application in 2001 and now submit an amendment to the
application using the eCTD backbone files, you do not have to go back and submit the document
information for the files submitted in 2001.
6

This includes mixed electronic and paper submissions.


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G.

Referencing Previously Submitted Documents7

If a document was submitted in electronic format with the eCTD backbone files, you should not
submit additional copies when referencing the previously submitted document. Instead, you
should include the information by reference by providing in the text of the document (1) the
application or master file number, (2) the date of submission (e.g., letter date), (3) the document
name, and (4) the page number of the referenced document along with a hypertext link to the
location of the information (see section II.Q of this guidance). If a document replaces or appends
a document previously submitted with an eCTD backbone file, then you should include this
information in the appropriate eCTD backbone file. The details on how to include this
information in the eCTD backbone file are provided in the associated specifications for eCTD
backbone files.
If a document was previously submitted in either paper or electronic format without the proper
eCTD backbone files, you should reference the document as with any paper submission. In the
text of the document, you should include (1) the application or master file number, (2) the date of
submission (e.g., letter date), (3) the document name, (4) the page number, and (5) the
submission identification (e.g., submission serial number, volume number, electronic folder, and
file name) of the referenced document. In such cases, providing an electronic copy of the
previously submitted documents can increase the utility of the submission. These documents,
like all documents in the submission, should be appropriately described in the eCTD backbone
files. These files are considered new in the eCTD backbone files.
When referring to documents that are part of other applications, please remember to include the
appropriate letters of authorization with the submission (e.g., 21 CFR 314.420(d)).
H.

Refuse to File

We may refuse to file an application or supplement under our regulations (e.g., 21 CFR 314.101
and 601.2) if the submission is illegible, uninterpretable, or otherwise clearly inadequate,
including having incompatible formats or inadequate organization. These regulations apply to
both paper and electronic submissions. The absence of electronic datasets in an acceptable
format to permit review and analysis may be considered inadequate, resulting in a refuse-to-file
decision.8 Following the recommendations in this guidance document will help ensure that your
electronic application meets the requirements of FDA regulations and can be archived,
processed, and reviewed within specified time frames using our tools.

Previously submitted documents include previously submitted information by reference for master files, market
applications, and investigational applications discussed under 21 CFR 312.23(a)(11)(b), 314.50(g)(1), 314.420(b),
and 601.51(a).

See more on this in CBER's SOPP 8404.


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Contains Nonbinding Recommendations


I.

Submission of Paper Copies

When providing applications in electronic format using the eCTD backbone files, paper copies of
the application, including review copies and desk copies, are not required and should not be sent.
J.

Scanned Documents

Scanned documents submitted electronically as images are not as useful for review as documents
that are text based. Image-based documents are more difficult to read and cannot be
electronically searched. It takes longer to print image-based documents, and they occupy more
storage space than text-based documents. For these reasons, we strongly urge that you provide
text-based documents, rather than image files, whenever possible. We understand that certain
documents may only be available as image files. Handwritten documents and documents that
were generated independent from the company, such as journal publications, may be available
only in paper. Documents that may only be available in paper can be scanned and submitted in
electronic format as image-based files. However, we expect documents such as study reports
recently generated by the company or recently generated as the result of the company's request to
be available as text-based documents. We understand that legacy study reports, those generated
years ago, may only be available in paper. For these reports, especially those for pivotal studies,
you may want to consider converting these documents from image files to text-based files.
Optical Character Recognition that has been validated is an option.
K.

The FDA District Office Copy

FDA District offices have access to documents submitted in electronic format. Therefore, when
sending submissions in electronic format, you need not provide any documentation to the FDA
Office of Regulatory Affairs District Office.
L.

Electronic Signatures

Documents required by regulations to be submitted with an original signature (e.g., FDA form
356h, FDA form 1571) should be submitted with electronic signatures that follow the controls
described under 21 CFR part 11.
M.

Number of Copies of Electronic Files

You should send a single copy of the electronic portions of a submission to the appropriate
central document room facility. Copies should not be sent directly to the reviewer or review
division. Electronic documents that bypass the controls for electronic files described in 21 CFR
11 are not considered official documents for review.
N.

Naming Electronic Files

To function properly, the eCTD backbone files must have specific names (e.g., index.xml,
us-regional.xml). For other files without a specified name, you should provide a name that is
indicative of the contents (e.g., protocol-101). The file name should allow a reviewer to infer

Contains Nonbinding Recommendations


some concept of the file's contents relative to other files. The file name should be less than or
equal to 64 characters including the appropriate file extension. You should use only letters
(lower case), numbers, or hyphens in the name. You should not use blank spaces. When naming
files, it is important to remember that to avoid truncation the length of the entire path of
the file should not exceed 230 characters.
O.

Naming Folders

The terms folder and subfolder are used in this guidance and are intended to be synonymous with
directory and subdirectory. The main submission, regional administrative folders, and certain
subfolders should have specific names for proper and efficient processing of the submission.
Recommendations regarding naming the main submission folders and regional administrative
folders can be found in section III, below. Other specific folder names can be found in the
specifications associated with this guidance. You can use only letters (lower case), numbers, or
hyphens in the name. You should not use blank spaces. The length of the folder name should not
exceed 64 characters. When naming folders, it is important to remember that the length of the
entire path should not exceed 230 characters. You should not include empty folders in the
submission.
P.

File Formats

We recommend that you send electronic documents in the file formats specified in this guidance.
We will not be able to manage, process, archive, or review documents provided in other file
formats.
The following file formats should be used:

PDF for reports and forms


SAS XPORT (version 5) transport files (XPT) for datasets
ASCII text files (e.g., SAS program files, NONMEM control files) using txt for the file
extension
XML for documents, data, and document information files
Stylesheets (XSL) and document type definition (DTD) for the XML document
information files
Microsoft Word for draft labeling (because Microsoft Word can change, check our Web
site for the current version)

In the future, we may consider other electronic file formats for use with electronic submissions,
or we may consider the use of the current formats with other electronic submissions. We intend
to publish guidance to advise on the use of file formats for specific types of submissions for use
in the future.

Contains Nonbinding Recommendations

Q.

PDF Bookmarks and Hypertext Links

For documents with a table of contents, provide bookmarks and hypertext links for each item
listed in the table of contents including tables, figures, publications, references, and associated
appendices. These bookmarks and hypertext links are essential for efficient navigation through
documents. You should make the bookmark hierarchy identical to the table of contents.
Navigation efficiency is also improved by providing hypertext links throughout the body of the
document to supporting annotations, related sections, references, appendices, tables, or figures
that are not located on the same page.
It is possible to link to other documents in a submission using relative paths when creating
hypertext linking. Absolute links that reference specific drives and root directories are not
functional once the submission is loaded onto the document repository. For example, the link
path ../../../123456/0001/.. will work, but the link c:\123456\0001\ will not work. However,
you should keep in mind that some documents may be subsequently replaced or appended,
possibly rendering the link obsolete, so linking should be used cautiously.
When creating bookmarks and hypertext links, choose the magnification setting Inherit Zoom so
that the destination page displays at the same magnification level that the reviewer is using for
the rest of the document.
R.

Sending Electronic Submissions

All submissions provided in electronic format must be sent to the appropriate central document
room facility for processing to maintain the integrity of the submission as required under 21 CFR
part 11. Electronic documents sent directly to division document rooms or to reviewers bypass
the controls established for the receipt and archiving of documents and are not considered
official documents for review. See the associated specifications for more information, including
electronic transmission.
S.

Technical Problems or Questions

If you have any questions on technical issues related to providing electronic submissions
according to the recommendations in this guidance, contact the electronic submission
coordinator at esub@cder.fda.gov. Specific technical issues related to submissions to CBER
should be sent to esubprep@cber.fda.gov. Specific questions pertaining to content should be
directed to the appropriate review division or office.
III.

ORGANIZING THE MAIN SUBMISSION FOLDER

All documents in the electronic submission should be placed in a main submission folder using a
four-digit sequence number for the application with the original submission for an application
designated 0000. You should assign numbers for each submission to the same application with
consecutive numbers. For example, the folder for the 3rd submission to an application, whether it

Contains Nonbinding Recommendations


is an amendment, supplement, or general correspondence is numbered 0002. The 4th submission
is numbered 0003. This also applies to applications where previous submissions were not based
on the ICH eCTD specifications. For example, if the submission is the 25th and the previous 24
were in paper, you would number the folder 0024. You should place the eCTD backbone file for
modules 2 to 5 for the submission in this folder (index.xml). You should place the checksum file
(e.g., index-md5.txt) in the same folder. Sequence numbers are used to differentiate between
submissions for the same application and do not need to correspond to the order they are
received by the Agency.
We recommend that you use subfolders to organize files in a submission, including for each
module m1, m2, m3, m4, and m5, respectively. There is a subfolder util to organize eCTD
technical files in the submission. Place these subfolders in the sequence number folder (e.g.,
folder named 0000 for the initial submission to an application). Do not include empty subfolders.
The following sections provide guidance for organizing the folders and files in the m1, m2, m3,
m4, m5, and util folders. In addition, you can find instructions on preparing the submission of an
electronic application to CBER at http://www.fda.gov/cber/esub/esub.htm.
A.

Module 1 Administrative Information and Prescribing Information Folder

Module 1 contains administrative and labeling documents. The organization of the documents in
module 1 is the same for all applications and related submissions. The subject matter for each
document should be assigned to the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. Note that some
headings apply only to specific applications or specific submissions. You should create a folder
named us and place it in the folder named m1. The documents for module 1 should be placed in
the us folder including the us-regional.xml file pertaining to the eCTD backbone files for module
1. Below are some additional details on providing specific types of documents.
1.

eCTD backbone document information files

The details on creating this file are in the associated document eCTD Backbone Files
Specification for Module 1.
2.

Cover letter (optional)

If you decide to include a cover letter, we recommend you include the following information:

Description of the submission including appropriate regulatory information


Description of the submission including the approximate size of the submission (e.g., 2
gigabytes), the format used for DLT tapes, and the type and number of electronic media
used (e.g., three CDROMs), if applicable
Statement that the submission is virus free with a description of the software (name,
version, and company) used to check the files for viruses
Regulatory and technical point of contact for the submission
9

Contains Nonbinding Recommendations

3.

Labeling

The following section describes how to provide specific labeling documents.


a.

Labeling history

You can provide a history summarizing labeling changes as a single PDF file. The
following information will help us confirm changes made to the labeling:

b.

Complete list of the labeling changes being proposed in the current


submission and the explanation for the changes
Date of the last approved labeling
History of all changes since the last approved labeling. With each change,
you should note the submission that originally described the change and the
explanation for the change.
List of supplements pending approval that may affect the review of the
labeling in the current submission
Content of labeling

See the guidance for industry on Providing Regulatory Submissions in Electronic


Format Content of Labeling for details on providing the content of labeling
files.
c.

Labeling samples

Each labeling sample (e.g., carton labels, container labels, package inserts) should
be provided as individual PDF files. The samples should (1) include all panels, if
applicable; (2) be provided in their actual size; and (3) reflect the actual color
proposed for use.
4.

Advertisements and promotional material

Advertisements and promotional labeling include material submitted under 21 CFR


314.81(b)(3)(i) or 601.12(f)(4) as part of the postmarketing reporting regulations for approved
applications, submitted under the requirements of 21 CFR 314.550 and 601.45 (part of the
accelerated approval requirements and restricted distribution for drug and biological products),
or voluntarily submitted to INDs. You should submit promotional material to the appropriate
application. You should not mix submissions of advertisements and promotional labeling with
submissions containing other types of information.
Each promotional piece should be provided as an individual PDF file. In cases when
promotional writing or images cover more than one page (e.g., a brochure spread), the reviewer
should be able to view the entire layout at one time. For three-dimensional objects, you should
provide a digital image of the object in sufficient detail to allow us to review the promotional
10

Contains Nonbinding Recommendations


material. In addition, you should provide information adequate to determine the size of the object
(e.g., point size, dimensions). A dimensional piece shown flat, such as a flattened carton, can
also be submitted.
If you choose to include cover letters with your submissions of advertising and promotional
material, they should be provided as individual PDF files and indicate for the reviewer any
additional important information, such as which materials need priority reviews.
If references are provided, each reference should be submitted as an individual PDF file and
placed in the appropriate module based on subject matter. If possible, you should highlight the
sections of the full reference that you refer to in the promotional materials. When a reference is
used to support a claim in proposed promotional materials voluntarily submitted for advisory
opinion or Agency comment, you should provide a hypertext link to the page of the reference or
labeling that contains the supporting information.
For promotional materials submitted as part of the postmarketing reporting requirements, you
may choose to provide hypertext links to references or labeling. References improve the
efficiency of a review.
5.

Marketing annual reports

In the postmarketing study commitments files, you should include a bookmark for each study
described.
6.

Information amendments

You should include documents that are provided in information amendments in the appropriate
module using the appropriate headings to describe the subject matter. In the unusual case when
information amendments do not fit appropriately under any heading in the CTD, you should
place the documents in module 1 under the heading information amendment: Information not
covered under modules 2 to 5. You should provide a separate PDF file for each subject
covered. Documents that apply to more than one module should be placed under the heading
Multiple module information amendments.
B.

Module 2 Summary Folder

You should place the documents for module 2 in the m2 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. Each document should
be provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic
Common Technical Document Specification are not necessary for the review of the submission.
If you choose to use the additional subfolder, we will maintain the subfolder structure so links
will function properly.

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Contains Nonbinding Recommendations


C.

Module 3 Quality Folder

The organization of the module 3 folder is the same for all applications and related submissions.
You should place the documents for module 3 in the m3 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. Each document should
be provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic
Common Technical Document Specification are not necessary for the review of the submission.
If you choose to use the additional subfolder, we will maintain the subfolder structure used so
links will function properly.
You should provide the files pertaining to Key Literature References (CTD section 3.3) as
individual PDF files. The filenames should be short and meaningful.
D.

Module 4 Safety Folder

The organization of the module 4 folder is the same for all applications and related submissions.
You should place the documents for module 4 in the m4 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. The headings for study
reports should also be specific for the lowest level of the hierarchy. Each document should be
provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic
Common Technical Document Specification are not necessary for the review of the submission.
If you choose to use the additional subfolder, we will maintain the subfolder structure so links
will function properly.
1.

Study reports

Typically, a single document should be provided for each study report included in this module.
However, if you provide the study reports as multiple documents, you should confine the subject
matter of each document to a single item in the following list.

Synopsis
Study report body
Protocol and amendments
Signatures of principal or coordinating investigator(s)
Audit certificates and reports
Documentation of statistical methods and interim analysis plans
Documentation of interlaboratory standardization methods of quality assurance
procedures if used
Publications based on the study
Important publications referenced in the report
Compliance and/or drug concentration data
Individual subject data listings
Data tabulations
- Data tabulations datasets
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- Data definitions
Data listing
- Data listing datasets
- Data definitions
Analysis datasets
- Analysis datasets
- Analysis programs
- Data definitions
IND safety reports
In the following examples, you should provide the study reports as separate documents

Documents previously submitted. If you have provided a document in a previous


submission (e.g., protocol), you should provide a reference to the protocol, not resubmit
the protocol.
Additional information added. If you think you will want to add information to the
study report over time (e.g., audit information, publication based on the study), you
should provide the study reports as separate documents and then the new information
can be provided as a separate file, rather than replacing the entire study report.
Different file formats. If you submit the individual animal data listings as datasets (e.g.,
SAS transport files), you should provide these as separate files from the study reports
(e.g., submitted as PDF files).

When providing a study report, you should include the study tagging file (STF) described in the
associated document The eCTD Backbone File Specifcation for Study Tagging Files.
2.

Literature references

You should provide each literature reference as an individual PDF file. The filenames should be
short and meaningful.
3.

Datasets

See the associated document Study Data Specifications for details on providing datasets and
related files (e.g., data definition file, program files)
E.

Module 5 Clinical Study Reports Folder

The organization of the module 5 folder is the same for all applications and related submissions.
You should place the documents for module 5 in the m5 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. One exception is that
legacy study reports can be provided as a single document. Each document should be provided as
an individual PDF file. The subfolders described in the guidance M2 eCTD: Electronic Common
Technical Document Specification are not necessary for the review of the submission. If you

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Contains Nonbinding Recommendations


choose to use the additional subfolder, we will maintain the subfolder structure so links will
function properly.
1.

Tabular listing of all clinical studies

You should provide the tabular listing of all clinical studies as a single PDF file.
2.

Study reports

Typically, clinical study reports are provided as more than one document based on the ICH E3
guidance document when providing a study.9 In addition, if you have provided a document in a
previous submission (e.g., protocol), you should provide a reference to the protocol rather than
resubmitting the protocol. In cases when a legacy report has already been prepared as a single
electronic document, you can provide the entire study report, other than the case report forms
(CRFs) and individual data listings, as a single document. The individual documents that should
be included in a study report are listed below:

Synopsis10 (E3 2)
Study report (E3 1, 3 to 15)
Protocol and amendments (E3 16.1.1)
Sample case report forms (E3 16.1.2)
List of IECs or IRBs (E3 16.1.3) and consent forms
List and description of investigators (E3 16.1.4) and sites
Signatures of principal or coordinating investigator(s) or sponsors responsible
medical officer (E3 16.1.5)
Listing of patients receiving test drug(s) from specified batch (E3 16.1.6)
Randomizations scheme (E3 16.1.7)
Audit certificates (E3 16.1.8) and reports
Documentation of statistical methods (E3 16.1.9) and interim analysis plans
Documentation of interlaboratory standardization methods of quality assurance
procedures if used (E3 16.1.10)
Publications based on the study (E3 16.1.11)
Important publications referenced in the report (E3 16.1.12)
Discontinued patients (E3 16.2.1)
Protocol deviations (E3 16.2.2)
Patients excluded from the efficacy studies (E3 16.2.3)
Demographic data (E3 16.2.4)
Compliance and/or drug concentration data (E3 16.2.5)
Individual efficacy response data (E3 16.2.6)
Adverse event listings (E3 16.2.7)
Listing of individual laboratory measurements by patient (E3 16.2.8)

When providing a study report, you should include the study tagging file (STF) described in the associated
document The eCTD Backbone File Specification for Study Tagging Files.
10

The synopsis should be provided as a document separate from the study report.
14

Contains Nonbinding Recommendations

3.

Case report forms (E3 16.3)


Individual patient data listings (CRTs) (E3 16.4)
Data tabulations
- Data tabulations datasets
- Data definitions
- Annotated case report form
Data listing
- Data listing datasets
- Data definitions
- Annotated case report form
Analysis datasets
- Analysis datasets
- Analysis programs
- Data definitions
- Annotated case report form
Subject profiles
IND safety reports
Case report forms

You should provide an individual subjects complete CRF as a single PDF file. If a paper CRF
was used in the clinical trial, the electronic CRF should be a scanned image of the paper CRF
including all original entries with all modifications, addenda, corrections, comments,
annotations, and any extemporaneous additions. If electronic data capture was used in the
clinical trial, you should submit a PDF-generated form or other PDF representation of the
information (e.g., subject profile).
You should use the subjects unique identifier as the title of the document and the file name.
These names are used to assist reviewers in finding the CRF for an individual subject. Each CRF
must have bookmarks as part of the comprehensive table of contents required under
21 CFR 314.50(b). We recommend bookmarks for each CRF domain and study visit to help the
reviewer navigate the CRFs. For addenda and corrections, making a hypertext link from the
amended item to the corrected page or addendum is a useful way to avoid confusion. Bookmarks
for these items should be displayed at the bottom of the hierarchy.
4.

Datasets

See the associated document Study Data Specifications for details on providing datasets and
related files (e.g., data definition files, program files). For subject profiles, you should use the
subjects unique identifier in the title of the document and the file name.
5.

Periodic safety update reports

To facilitate electronic submissions, we have divided the postmarketing periodic adverse drug
experience report into three parts: (1) individual case safety reports (ICSRs), (2) ICSR
attachments, if applicable, and (3) descriptive information. The descriptive information includes

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Contains Nonbinding Recommendations


the narrative summary and analysis of the information in the report (i.e., periodic ICSRs and
ICSR attachments), an analysis of the 15-day alert reports submitted during the reporting interval
(i.e., expedited ICSRs and ICSR attachments), and the history of actions taken since the last
report because of adverse drug experiences (e.g., labeling changes, studies initiated) as described
in 21 CFR 314.80(c)(2)(ii)(a) and (c) and 600.80(c)(2)(ii)(A) and (C)). You should supply the
descriptive information as an individual PDF file. You should provide bookmarks for each of the
sections and subsections of this report. ICSR and ICSR attachments should be provided as
described in the guidance for industry Providing Regulatory Submissions in Electronic Format
Postmarketing Periodic Adverse Drug Experience Reports.
6.

Literature references

You should provide each literature reference as an individual PDF file. The filenames should be
short and meaningful.
IV.

UTILITY FOLDER

You should create two folders, dtd and style and place them in the util folder.
A.

Document Type Definition Folder

You should place the document type definition (DTD) that you used to create the eCTD
backbone file (index.xml), the DTD you used to create the FDA Regional eCTD backbone file
(us-regional.xml), and the DTD used for the STF in the folder named dtd. You should use the
most recent DTD.11
B.

Style Folder

You should use the most recent stylesheet. See the guidance for industry M2 eCTD: Electronic
Common Technical Document Specification.

11

See the FDA Web site at http://www.fda.gov/cder/regulatory/ersr/.


16

Part 4
Technical Requirements

SECTION 6

Comprehensive eCTD Table of


Contents Headings and Hierachy

This section includes the complete structure and numbering for content headings and
the hierarchy of Modules 15.

Comprehensive Table of Contents Headings and Hierarchy

Comprehensive Table of Contents Headings and Hierarchy

Revision History

Date
Version
Summary of Changes
2004-07
1.0
Original version
2005-06-16
1.1
Corrections and additions to the mapping tables
2005-07-06
1.2
Corrections to the headings

Module 1 Administrative information


1.1 Forms
1.1.1 Application form: FDA form 1571
1.1.2 Application form: FDA form 356h
1.1.3 User fee cover sheet: FDA form 3397
1.1.4 Annual report transmittal: FDA form 2252
1.1.5 Advertisements and promotional labeling transmittal: FDA
form 2253
1.1.6 Transmittal of Labels and Circulars: FDA form 2567
1.2 Cover letters
1.3 Administrative information
1.3.1 Contact/sponsor/Applicant information
1.3.1.1 Change of address or corporate name
1.3.1.2 Change in contact/agent
1.3.1.3 Change in sponsor
1.3.1.4 Transfer of obligation
1.3.1.5 Change in ownership of an application
1.3.2 Field copy certification
1.3.3 Debarment certification
1.3.4 Financial certification and disclosure
1.3.5 Patent and exclusivity
1.3.5.1 Patent information
1.3.5.2 Patent certification
1.3.5.3 Exclusivity request
1.4 References
1.4.1 Letter of authorization
1.4.2 Statement of right of reference
1.4.3 List of authorized persons to incorporate by reference
1.4.4 Cross reference to other applications
1.5 Application status
1.5.1 Withdrawal request
1.5.2 Inactivation request
1.5.3 Reactivation request
1.5.4 Reinstatement request
1.5.5 Withdrawal of an unapproved NDA
1.5 6 Withdrawal of listed drug
1.5.7 Request for withdrawal of application approval
1.6 Meetings
1.6.1 Meeting request
1.6.2 Meeting background materials
1

Comprehensive Table of Contents Headings and Hierarchy

1.6.3 Correspondence regarding meetings


1.7 Fast track
1.7.1 Fast track designation request
1.7.2 Fast track designation withdrawal request
1.7.3 Rolling review request
1.8 Special protocol assessment request
1.8.1 Clinical study
1.8.2 Carcinogenicity study
1.8.3 Stability study
1.9 Pediatric administrative information
1.9.1 Request for waiver of pediatric studies
1.9.2 Request for deferral of pediatric studies
1.9.3 Request for pediatric exclusivity determination
1.9.4 Proposed pediatric study request and amendments
1.9.5 Proposal for written agreement
1.9.6 Other correspondence regarding pediatric exclusivity or
study plans
1.10 Dispute resolution
1.10.1 Request for dispute resolution
1.10.2 Correspondence related to dispute resolution
1.11 Information amendment: Information not covered under
modules 2 to 5
1.11.1 Quality information amendment
1.11.2 Safety information amendment
1.11.3 Efficacy information amendment
1.12 Other correspondence
1.12.1 Pre IND correspondence
1.12.2 Request to charge
1.12.3 Notification of charging under treatment IND
1.12.4 Request for comments and advice
1.12.5 Request for a waiver
1.12.6 Exemption from informed consent for research
1.12.7 Public disclosure statement for exception from informed
consent for research
1.12.8 Correspondence regarding exception from informed
consent for research
1.12.9 Notification of discontinuation of clinical trial
1.12.10 Generic drug enforcement act statement
1.12.11 Basis for submission statement
1.12.12 Comparison of generic drug and reference listed drug
1.12.13 Request for waiver for in vivo studies
1.12.14 Environmental analysis
1.12.15 Request for waiver of in vivo bioavailability studies
1.12.16 Field alert reports
1.13 Annual report
1.13.1 Summary for nonclinical studies

Comprehensive Table of Contents Headings and Hierarchy

1.13.2 Summary of clinical pharmacology information


1.13.3 Summary of safety information
1.13.4 Summary of labeling changes
1.13.5 Summary of manufacturing changes
1.13.6 Summary of microbiological changes
1.13.7 Summary of other significant new information
1.13.8 Individual study information
1.13.9 General investigational plan
1.13.10 Foreign marketing history
1.13.11 Distribution data
1.13.12 Status of postmarketing study commitments
1.13.13 Status of other postmarketing studies
1.13.14 Log of outstanding regulatory business
1.14 Labeling
1.14.1 Draft labeling
1.14.1.1 Draft carton and container labels
1.14.1.2 Annotated draft labeling text
1.14.1.3 Draft labeling text
1.14.1.4 Label comprehension studies
1.14.1.5 Labeling history
1.14.2 Final labeling
1.14.2.1 Final carton or container labels
1.14.2.2 Final package insert (package inserts,
patient information, Medication guides)
1.14.2.3 Final labeling text
1.14.3 Listed Drug Labeling
1.14.3.1 Annotated comparison with listed drug
1.14.3.2 Approved labeling text for listed drug
1.14.3.3 Labeling text for reference listed drug
1.14.4 Investigational drug labeling
1.14.4.1 Investigational brochure
1.14.4.2 Investigational drug labeling
1.14.5 Foreign labeling
1.15 Promotional material
1.16 Risk management plans

Module 2 Summaries
2.2 Introduction to summary
2.3 Quality overall summary
2.4 Nonclinical overview
2.5 Clinical overview
2.6 Nonclinical written and tabulated summaries
2.6.1 Introduction
2.6.2 Pharmacology written summary
2.6.3 Pharmacology tabulated summary
2.6.4 Pharmacokinetic written summary
2.6.5 Pharmacokinetic tabulated summary

Comprehensive Table of Contents Headings and Hierarchy

2.6.6 Toxicology written summary


2.6.7 Toxicology tabulated summary
2.7 Clinical summary
2.7.1 Summary of Biopharmaceutic Studies and Associated
Analytical Methods
2.7.2 Summary of Clinical Pharmacology studies
2.7.3 Summary of Clinical Efficacy [indication]
2.7.4 Summary of Clinical Safety
2.7.5 References
2.7.6 Synopses of individual studies

Module 3 Quality
3.2 Body of data
3.2.S Drug Substance [name, manufacturer]
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General properties

3.2.S.2 Manufacture

3.2.S.2.1 Manufacturer(s)
3.2.S.2.2 Description of Manufacturing Process and Process
Controls
3.2.S.2.3 Control of Materials
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and/or Evaluation
3.2.S.2.6 Manufacturing Process Development

3.2.S.3 Characterization

3.2.S.3.1 Elucidation of Structure and other Characteristics


3.2.S.3.2 Impurities

3.2.S.4 Control of Drug Substance

3.2.S.4.1 Specification
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justification of Specification

3.2.S.5 Reference Standards or Materials


3.2.S.6 Container Closure Systems
3.2.S.7 Stability

3.2.S.7.1 Stability Summary and Conclusions


3.2.S.7.2 Post Approval Stability Protocol and Stability
Commitment
3.2.S.7.3 Stability Data

3.2.P Drug product [name, dosage form, manufacturer]


3.2.P.1 Description and Composition of the Drug
Product
3.2.P.2 Pharmaceutical Development
3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer(s)
3.2.P.3.2 Batch Formula

Comprehensive Table of Contents Headings and Hierarchy

3.2.P.3.3 Description of Manufacturing Process and Process


Controls
3.2.P.3.4 Controls of Critical Steps and Intermediates
3.2.P.3.5 Process Validation and/or Evaluation

3.2.P.4 Control of Excipients [name]

3.2.P.4.1 Specification(s)
3.2.P.4.2 Analytical Procedures
3.2.P.4.3 Validation of Analytical Procedures
3.2.P.4.4 Justification of Specifications
3.2.P.4.5 Excipients of Human or Animal Origin
3.2.P.4.6 Novel Excipients

3.2.P.5 Control of Drug Product

3.2.P.5.1 Specification(s)
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of Analytical Procedures
3.2.P.5.4 Batch Analyses
3.2.P.5.5 Characterization of Impurities
3.2.P.5.6 Justification of Specification(s)

3.2.P.6 Reference Standards or Materials


3.2.P.7 Container Closure System
3.2.P.8 Stability

3.2.P.8.1 Stability Summary and Conclusion


3.2.P.8.2 Post-approval Stability Protocol and Stability
Commitment
3.2.P.8.3 Stability Data

3.2.A Appendices
3.2.A.1 Facilities and Equipment [name,
manufacturer]
3.2.A.2 Adventitious Agents Safety Evaluation [name,
dosage form, manufacturer]
3.2.A.3 Novel Excipients
3.2.R Regional Information
3.3Literature references

Module 4 Nonclinical Study Reports


4.2 Study reports
4.2.1 Pharmacology
4.2.1.1 Primary pharmacodynamics

Study report [identification number] and related information


Legacy study report
Synopsis
Study report body
Protocol and amendments
Signatures of principal or coordinating
investigator(s)
Audit certifications and reports
Documentation of statistical methods and interim
analysis plans
Documentation of inter laboratory standardization
methods of quality assurance procedures if used

Comprehensive Table of Contents Headings and Hierarchy

Publications based on the study


Important publications referenced in the report
Compliance and/or drug concentration data
Individual subject data listings
Data tabulation
Data tabulation datasets
Data definitions
Data listing datasets
Data listing datasets
Data definitions
Analysis datasets
Analysis datasets
Analysis programs
Data definitions
IND safety reports

4.2.1.2 Secondary pharmacodynamics

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for headings

4.2.1.3 Safety pharmacology

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.1.4 Pharmacodynamic drug interactions

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.2 Pharmacokinetics
4.2.2.1 Analytical methods and validation reports

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.2.2 Absorption

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.2.3 Distribution

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.2.4 Metabolism

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.2.5 Excretion

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.2.6 Pharmacokinetic drug interactions

Study report [identification number] and related information

Comprehensive Table of Contents Headings and Hierarchy

See Primary pharmacodynamics Study report and


related information for heading
Statement of QA differences

4.2.2.7 Other pharmacokinetic studies

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.3 Toxicology
4.2.3.1 Single dose toxicity [Species and route]

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.3.2 Repeat dose toxicity [Species, route, duration]


Study report [identification number] and related information
See Primary pharmacodynamics Study report and
related information for heading

4.2.3.3 Genotoxicity

4.2.3.3.1 In vitro
Study report [identification number] and related
information
See Primary pharmacodynamics Study
report and related information for heading

4.2.3.3.2 In vivo
Study report [identification number] and related
information

See Primary pharmacodynamics Study


report and related information for heading

4.2.3.4 Carcinogenicity

4.2.3.4.1 Long term studies [Species]


Study report [identification number] and related
information
See Primary pharmacodynamics Study
report and related information for heading

4.2.3.4.2 Short or medium term studies


Study report [identification number] and related
information

See Primary pharmacodynamics Study


report and related information for heading

4.2.3.4.3 Other studies


Study report [identification number] and related
information

See Primary pharmacodynamics Study


report and related information for heading

4.2.3.5 Reproductive and developmental toxicity

4.2.3.5.1 Fertility and early embryonic development


Study report [identification number] and related
information
See Primary pharmacodynamics Study
report and related information for heading

4.2.3.5.2 Embryofetal development

Comprehensive Table of Contents Headings and Hierarchy

Study report [identification number] and related


information
See Primary pharmacodynamics Study
report and related information for heading

4.2.3.5.3 Prenatal and postnatal development, including


maternal function
Study report [identification number] and related
information

See Primary pharmacodynamics Study


report and related information for heading

4.2.3.5.4 Studies in which the offspring (juvenile animals)


are dosed and/or further evaluated
Study report [identification number] and related
information
See Primary pharmacodynamics Study
report and related information for heading

4.2.3.6 Local tolerance

Study report [identification number] and related information


See Primary pharmacodynamics Study report and
related information for heading

4.2.3.7 Other toxicity studies

4.2.3.7.1 Antigenicity
Study report [identification number] and related
information
See Primary pharmacodynamics Study
report and related information for heading

4.2.3.7.2 Immunotoxicity
Study report [identification number] and related
information

See Primary pharmacodynamics Study


report and related information for heading

4.2.3.7.3 Mechanistic studies


Study report [identification number] and related
information

See Primary pharmacodynamics Study


report and related information for heading

4.2.3.7.4 Dependence
Study report [identification number] and related
information

See Primary pharmacodynamics Study


report and related information for heading

4.2.3.7.5 Metabolites
Study report [identification number] and related
information

See Primary pharmacodynamics Study


report and related information for heading

4.2.3.7.6 Impurities
Study report [identification number] and related
information
4.2.3.7.7 Other

See Primary pharmacodynamics Study


report and related information for heading

Comprehensive Table of Contents Headings and Hierarchy

Study report [identification number] and related


information
See Primary pharmacodynamics Study
report and related information for heading

4.3 Literature references

Module 5 Clinical Study Reports


5.2 Tabular listing of all clinical studies
5.3 Clinical study reports and related information
5.3.1 Reports of biopharmaceutic studies
5.3.1.1 Bioavailability (BA) Study reports and related
information

Study report [identification] and related information


Legacy study report
Synopsis (E3 2)
Study report (E3 1, 3 to 15)
Protocol and amendments (E3 16.1.1)
Sample case report form (E3 16.1.2)
List of IECs or IRBs (E3 16.1.3) and consent forms
List and description of investigators (E3 16.1.4) and
sites
Signatures of principal or coordinating
investigator(s) or sponsors responsible medical
officer (E3 16.1.5)
Listing of patients receiving test drug(s) from
specified batch (E3 16.1.6)
Randomisations scheme (E3 16.1.7)
Audit certificates (E3 16.1.8) and reports
Documentation of statistical methods (E3 16.1.9)
and interim analysis plans
Documentation of inter laboratory standardization
methods of quality assurance procedures if used (E3
16.1.10)
Publications based on the study (E3 16.1.11)
Important publications referenced in the report (E3
16.1.12)
Discontinued patients (E3 16.2.1)
Protocol deviations (E3 16.2.2)
Patients excluded from the efficacy analysis (E3
16.2.3)
Demographic data (E3 16.2.4)
Compliance and/or drug concentration data (E3
16.2.5)
Individual efficacy response data (E3 16.2.6)
Adverse event listings (E3 16.2.7)
Listing of individual laboratory measurements by
patient (E3 16.2.8)
Case report forms (E3 16.3)
Site [identifier]

Individual patient data listings (E3 16.4)


Data tabulation

Comprehensive Table of Contents Headings and Hierarchy

Data tabulation datasets


Data definitions
Data listing datasets
Data listing datasets
Data definitions
Analysis datasets
Analysis datasets
Analysis programs
Data definitions
Annotated CRF
Annotated ECG waveform datasets
Image files
Subject profiles
IND safety reports

5.3.1.2 Comparative BA and bioequivalence (BE)


Study reports and related information
Study report [identification] and related information
See example under bioavailability (BA) Study
reports and related information for headings

5.3.1.3 In Vitro - in Vivo correlation Study reports and


related information
Study report [identification] and related information
See example under bioavailability (BA) Study
reports and related information for headings

5.3.1.4 Reports of bioanalytical and analytical


methods for human studies

Study report [identification] and related information


See example under bioavailability (BA) Study
reports and related information for headings

5.3.2 Reports of studies pertinent to pharmacokinetics using


human biomaterials
5.3.2.1 Plasma protein binding Study reports and
related information
Study report [identification] and related information
See example under bioavailability (BA) Study
reports and related information for headings

5.3.2.1 Reports of hepatic metabolism and drug


interaction studies

Study report [identification] and related information


See example under bioavailability (BA) Study
reports and related information for headings

5.3.2.3 Reports of studies using other human


biomaterials

Study report [identification] and related information


See example under bioavailability (BA) Study
reports and related information for headings

5.3.3 Reports of human pharmacokinetic (PK) studies


5.3.3.1 Healthy subject PK and initial tolerability
Study reports and related information
Study report [identification] and related information

10

Comprehensive Table of Contents Headings and Hierarchy

See example under bioavailability (BA) Study


reports and related information for headings

5.3.3.2 Patient PK and initial tolerability Study reports


and related information
Study report [identification] and related information
See example under bioavailability (BA) Study
reports and related information for headings

5.3.3.3 Intrinsic factor PK Study reports and related


information
Study report [identification] and related information
See example under bioavailability (BA) Study
reports and related information for headings

5.3.3.4 Extrinsic factor Study reports and related


information
Study report [identification] and related information
See example under bioavailability (BA) Study
reports and related information for headings

5.3.3.5 Population PK Study reports and related


information

Study report [identification] and related information


See example under bioavailability (BA) Study
reports and related information for headings

5.3.4 Reports of human pharmacodynamic (PD) studies


5.3.4.1 Healthy subject PD and PK/PD Study reports
and related information
Study report [identification] and related information
See example under bioavailability (BA) Study
reports and related information for headings

5.3.4.2 Patient PD and PK/PD Study reports and


related information

Study report [identification] and related information


See example under bioavailability (BA) Study
reports and related information for headings

5.3.5 Reports of efficacy and safety studies [Indication]


5.3.5.1 Study reports and related information of
controlled clinical studies pertinent to the claimed
indication [type of control]
Study report [identification] and related information

See example under bioavailability (BA)


Study reports and related information for
headings

5.3.5.2 Study reports and related information of


uncontrolled clinical studies

Study report [identification] and related information


See example under bioavailability (BA) Study
reports and related information for headings

5.3.5.3 Reports of analyses of data from more than


one study
Integrated analysis of safety

11

Comprehensive Table of Contents Headings and Hierarchy

Integrated summary of safety report


Analysis datasets
Analysis programs
Integrated analysis of efficacy
Integrated summary of efficacy report
Analysis datasets
Analysis programs

5.3.5.4 Other Study reports and related information

Antibacterial microbiology reports


Special pathogens (e.g., fungi, parasites, mycobacteria) and
immune modulator reports
Antiviral reports

5.3.6 Reports of postmarketing experience


Postmarketing periodic adverse event drug
experience report description
5.4 Literature references

Mapping
IND

CFR Citation/Source
NUMBER
TITLE
FDAMA
FDAMA
FDAMA
PDUFA
agreements
FDAMA
PDUFA
agreements
PDUFA
agreements
PREA
PREA
BPCA
BPCA

CTD /*STF Heading


NUMBER
TITLE

Mod
ule
1

1.7.1

1.7.2

1.7.3

Rollin Review Request

1.7.5

Special protocol
assessment request:
Clinical study
Special protocol
assessment request:
Carcinogenicity Study
Special protocol
assessment request:
Stability study
Request for waiver of
pediatric studies
Request for deferral of
pediatric studies
Proposed Proposed
pediatric study request
and amendments
Proposal for Written
Agreement

1.8.1

1.8.1

1.8.1

1.9.1

1.9.2

1.9.4

1.9.5

Fast Track Designation


Request
Fast Track Designation
Withdrawal Request
Rolling Review Request

12

Fast Track Designation


Request
Fast Track Designation
Withdrawal Request
Rolling Review
Request
Correspondence
regarding CMA Pilot 2
Special protocol
assessment request:
Clinical study
Special protocol
assessment request:
Carcinogenicity study
Special protocol
assessment request:
Stability study
Request for waiver of
pediatric studies
Request for deferral of
pediatric studies
Proposed Proposed
pediatric study request
and amendments
Proposal for Written
Agreement

Comprehensive Table of Contents Headings and Hierarchy

PREA
BPCA
312.7(d)(1)
312.10
312.23(a)1
312.23(a)(2)
312.23(a)(3)(i)
312.23(a)(3)(iiiii)
312.23(a)(3)(iv)
312.23(a)(5)
312.23(a)(6)
312.23(a)(7)(a),
(b) and (c)
312.23(a)(7)(a),
(b) and (c)
312.23(a)7(d)
312.23(a)(7)(iv)(
e)
312.23(a)(8)
312.23(a)(8)

312.23(a)(8)
312.23(a)(9)
312.23(a)(9)
312.23(a)(9)

Correspondence
regarding pediatric
exclusivity or PREA
requirements
Charging for and
commercialization of
investigational drugs
Waivers
Cover sheet (Form FDA
1571).
Table of contents
Introductory statement

1.9.6

1.12.3

1
1

1.12.5
1.1.1

Correspondence
regarding pediatric
exclusivity or study
plans
Request to charge
Request for a waiver
Application form:
FDA form 1571
N/A
Introduction to
summary
Clinical overall
summary
General investigational
plan
Investigator brochure
*Protocol [under
specific study]
Quality overall
summary

N/A
2

N/A
2.2

Introductory statement

2.5

A brief description of the


overall plan
Investigator brochure
Protocol

1.13.9

1
5

1.14.4.1
5.3

2.3

As needed

Quality [use
appropriate sections]

1.14.4.2

Environmental analysis
requirements
Pharmacology and
toxicology information
Pharmacology and
toxicology information

1.12.14

Investigational Drug
Labeling
Environmental analysis

2.4

Nonclinical overview

2.6

Pharmacology and
toxicology information
Previous human
experience
Previous human
experience
Previous human
experience

4.2

2.5

Nonclinical written and


tabulated summaries
[use appropriate
sections]
Study reports [use
appropriate sections]
Clinical overview

2.7

5.3

Chemistry,
manufacturing and
controls
Chemistry,
manufacturing and
controls
Labeling

13

Clinical summary [use


appropriate sections]
Clinical study reports
and related information
[use appropriate
sections]

Comprehensive Table of Contents Headings and Hierarchy

312.23(a)(10)(i)
312.23(a)(10)(ii)

Drug dependence and


abuse
Radioactive drugs

312.23(a)(10)(iv) Other information

2.7.4

2, 4
or 5
2, 3,
4 or 5
1, 2,
3, 4
or 5
1

As needed

1, 2,
3, 4,
or 5
5

As needed
5.3

As needed

312.23(a)(11)

Relevant information

312.23(b)

312.30(a)

Information previously
submitted by sponsor
Material in a foreign
language (English
Translations)
New protocol

312.30(b)

Changes in protocol

5.3

312.30(c)

New investigator

5.3

312.31(a)(1),

Information amendment:
Chemistry
Information amendment:
Chemistry -information
not covered under
Module 3

As needed

1.11.1

Information amendment:
Toxicology
Information amendment:
Toxicology - information
not covered under
Module 4

As needed

1.11.2

Information amendment:
Clinical
Information amendment:
Clinical - information not
covered under Module 5

As needed

1.11.3

Report regarding the


discontinuation of a
clinical investigation
Statement of the nature

1.12.9

1.2

312.23(c)

312.31(a)(1)

312.31(a)(1)
312.31(a)(1)

312.31(a)(1)
312.31(a)(1)

312.31(a)(2)
312.31(b)(1)

14

As needed
1.4.4

Summary of Clinical
Safety
Use appropriate
sections
Use appropriate
sections
Use appropriate
sections
Cross reference to other
applications
Use appropriate
sections
Protocol [under
specific study]
Protocol [under
specific study]
List and description of
investigators and sites
[under specific study]
Use appropriate
sections
Quality information
amendment (only for
information not
covered under Module
3
Use appropriate
sections
Safety information
amendment (only for
information not
covered under Module
4)
Use appropriate
sections
Efficacy information
amendment (only for
information not
covered under Module
5
Notification of
discontinuation of
clinical trial
Cover letter

Comprehensive Table of Contents Headings and Hierarchy

312.31(b)(3)
312.32
312.33(a)
312.33(b)(1)

312.33(b)(2)
312.33(b)(3)
312.33(b)(4)
312.33(b)(5)
312.33(b)(6)
312.33(b)(7)

312.33(b)(7)

312.33(c)
312.33(e)

and purpose of the


information amendment
Request for comment on
information amendment
IND safety reports
Annual report individual
study information
Annual Report: A
narrative or tabular
summary showing the
most frequent and most
serious adverse
experiences by the body
system
Annual Report: A
summary of all IND
safety reports
Annual Report: A list of
subjects who died
Annual Report: A list of
subjects who dropped
out
Annual Report: A brief
description of the drugs
actions
Annual Report: A list of
preclinical studies
Annual Report: A
summary of any
significant manufacturing
changes
Annual Report: A
summary of any
significant
microbiological
changes
Annual Report: A
description of the general
investigational plan
Annual Report: A
description of any
significant Phase 1
protocol modifications
made during the previous
years and.
15

1.12.4

Request for comments


and advice
*IND safety report
[under specific study]
Individual study
information
Summary of safety
information

5.3

1.13.8

1.13.3

1.13.3

Summary of safety
information

1.13.3

1.13.3

Summary of safety
information
Summary of safety
information

1.13.2

1.13.1

1.13.5

1.13.5

Summary of
microbiological
changes

1.13.9

General investigational
plan

5.3

*Protocol [under the


specific study]

Summary of clinical
pharmacology
information
Summary of
nonclinical studies
Summary of
manufacturing changes

Comprehensive Table of Contents Headings and Hierarchy

312.33(d)
312.33(f)

312.33(g)
312.35(a)(1)
312.35(a)(2)(i)
312.35(a)(2)(ii)
312.35(a)(2)(iii)
312.36

Annual Report:
Investigators brochure
Annual Report: A brief
summary of significant
foreign marketing
developments
Annual Report: Log of
outstanding
business(optional)
Treatment protocol
Treatment protocol:
Investigators brochure
Treatment protocol:
Technical information
Treatment protocol:
Compliance with
informed consent
Emergency use of an
investigational new drug

312.38

Withdrawal of an IND

312.41

Comment and advice on


an IND
Request for Inactive
status

312.45(a)
312.45(d)
312.47
PDUFA
Agreements
312.47
PDUFA
Agreements
312.47
PDUFA
Agreements
312.48
FDAMA
312.48
FDAMA
312.52

1.14.4.1

Investigator brochure

1.13.10

Foreign marketing
history

1.13.14

Log of outstanding
regulatory business

5.3

1.14.4.1

*Protocol [under
specific study]
Investigator brochure

3, 4,
5
5

As needed

1, 2,
3, 4,
5
1

As Needed

5.3

Use appropriate
sections
*List and description of
investigators and sites
[under specific study]
Use appropriate
sections

1.5.1

Withdrawal Request

1.12.4

1.5.2

Request for comments


and advice
Inactivation request

Request to resume
clinical investigation
under an inactive IND
Meeting request

1.5.3

Reactivation Request

1.6.1

Meeting request

Meeting background
material

1.6.2

Meeting background
material

Correspondence
regarding a meeting

1.6.3

Correspondence
regarding a meeting

Request for dispute


resolution
Correspondence related
to dispute resolution
Transfer of obligations to
a

1.10.1

1.10.2

1.3.1.3

Request for a dispute


resolution
Correspondence related
to dispute resolution
Transfer of obligation

16

Comprehensive Table of Contents Headings and Hierarchy

contract research
organization.
312.54

Exception from informed


consent for research

1.12.6

312.54

Public disclosure
exception from informed
consent for research

1.12.7

312.54

IRB disapproval of
exception from informed
consent for research

1.12.8

312.120(b)(1)

Foreign clinical studies


not conducted under the
IND: Investigators
qualification
Foreign clinical studies
not conducted under the
IND: Research facility
Foreign clinical studies
not conducted under the
IND:Detailed summary
Foreign clinical studies
not conducted under the
IND: A description of the
drug substance and drug
product
Foreign clinical studies
not conducted under the
IND: Conformance with
ethical principles

5.3

5.3

5.3

As needed

5.3

312.120(b)(2)
312.120(b)(3)
312.120(b)(4)

312.120(c)

NDA

CFR Citation/Source
NUMBER
TITLE
FDAMA
Fast Track Designation
Request
FDAMA
Fast Track Designation
Withdrawal Request
FDAMA
Rolling Review
Request
FDAMA
Correspondence
regarding Fast
Track/Rolling Review
PDUFA
Rolling Review
17

Module
1
1
1
1
1

Exception from
informed consent for
research
Public disclosure
statement for exception
from informed consent
for research
Correspondence
regarding exception
from informed consent
for research
*List and description of
investigators and sites
[under specific study]
*List and description of
investigators and sites
[under specific study]
Use appropriate
sections [under specific
study]
Use appropriate
sections

*List of IECs or IRBs


and consent forms
[under specific study]

CTD /*STF Heading


NUMBER
TITLE
1.7.1
Fast Track Designation
Request
1.7.2
Fast Track Designation
Withdrawal Request
1.7.3
Rolling Review
Request
1.7.4
Correspondence
regarding Fast
Track/Rolling Review
1.7.6
Correspondence

Comprehensive Table of Contents Headings and Hierarchy

agreements
314.50(a)

Request
Application form

1.1.2

PDUFA

User Fee Cover Sheet

1.1.3

GDEA

Debarment
Certification
Request for waiver of
pediatric studies
Request for deferral of
pediatric studies
Request for pediatric
exclusivity
determination
Proposed pediatric
study request and
amendments
Proposal for written
agreement
Correspondence
regarding pediatric
exclusivity or PREA
requirements
Index
The proposed text of
the labeling with
annotations
Summaries

1.3.3

1.9.1

1.9.2

1.9.3

1.9.4

1.9.5

1.9.6

PREA
PREA
BPCA
BPCA
BPCA
PREA
BPCA
315.50(b)
314.50(c)(2)(i)
314.50(c)(2)(ii)
to (ix)
314.50(d)(1)(i)
and (ii)

314.50(d)(4)

Chemistry,
manufacturing and
controls
Environmental impact
Field copy certification
Nonclinical
pharmacological and
toxicology section
Human
pharmacokinetics and
bioavailability sections
Microbiology

314.50(d)(5)(i)

Clinical data section

314.50(d)(1)(iii)
314.50(d)(1)(v)
314.50(d)(2)
314.50(d)(3)

18

N/A
1

N/A
1.14.1.2

regarding CMA Pilot 1


Application form: FDA
form 356h
User Fee Cover Sheet:
FDA form 3397
Debarment
Certification
Request for waiver of
pediatric studies
Request for deferral of
pediatric studies
Request for pediatric
exclusivity
determination
Proposed pediatric
study request and
amendments
Proposal for written
agreement
Correspondence
regarding pediatric
exclusivity or study
pland
N/A
Annotated draft
labeling text

As needed

As needed

1
1
4

1.12.14
1.3.2
As needed

Environmental analysis
Field copy certification
Use appropriate
sections

5.3

Use appropriate
sections

5.3.5.5

Other study reports and


related information
[Use appropriate
sections in
microbiology STF]
Use appropriate

5.3

Use the appropriate


sections
Use the appropriate
sections

Comprehensive Table of Contents Headings and Hierarchy

to (iv)
314.50(d)(5)(v)

An integrated summary
of efficacy

5.3.4

314.50(d)(5)(vi)(
a)

An integrated summary
of safety

5.3.4

314.50(d)(5)(vi)(
b)

Safety Update

5.3.5

314.50(d)(5)(vii)

Potential for abuse

5.3

314.50(d)(5)(viii
)
314.50(d)(5)(ix)

2.5

314.50(d)(5)(xi)

An integrated summary 2
of the benefits and risks
Statement of
5
compliance with
informed consent
Transfer of obligations
to CRO
Audited studies

314.50(d)(6)(i)
and (ii)

Description of
statistical analysis

314.50(d)(7)

Pediatric use section

2 and 5

As needed

314.50(e)(2)(i)

Analytical methods

As needed

314.50(e)(2)(ii)

Copies of the labeling


and all labeling for the
drug product
Case report tabulations

1.14

5.3

314.50(d)(5)(x)

314.50(f)(1)

19

5.3
1

1.3.1.4

5.3

5.3

sections
Reports of analysis of
data from more than
one study [Use
appropriate sections in
integrated summary of
efficacy STF]
Reports of analysis of
data from more than
one study [Use
appropriate sections in
integrated summary of
safety STF]
Reports of analysis of
data from more than
one study [Use
appropriate sections in
integrated summary of
safety STF]
Use appropriate
sections
Use appropriate
sections
*List of IECs or IRBs
and consent forms
[under specific study]
Transfer of obligation
*Audit certificates and
reports [under specific
study]
*Documentation of
statistical methods and
interim analysis plans
[under specific study]
Use appropriate
sections
Use appropriate
sections
Use appropriate
sections
*Case report
tabulations [use the
appropriate sections
under the specific

Comprehensive Table of Contents Headings and Hierarchy

study]
*Case report forms
[under the appropriate
site and specific study]
Letter of authorization

314.50(f)(2)

Case report forms

5.3

314.50(g)(1)

Written statement of
authorization for
references
Reference to
information previously
submitted by sponsor

1.4.1

1.4.4

Statement of right of
reference
Patent Information

1.4.2

1.3.5.1

Patent certification

1.3.5.2

Claimed exclusivity
Financial certification
and disclosure
statement
Pediatric studies:
waiver of pediatric
study requirements
Pediatric studies:
deferrals of pediatric
study requirements
Amendment to an
unapproved
application: Chemistry
Amendment to an
unapproved
application: Chemistry
(information not
covered under Module
3)
Amendment to an
unapproved
application: Toxicology
Amendment to an
unapproved
application: Toxicology
(information not
covered under Module
4)

1
1

1.3.5.3
1.3.4

Exclusivity claim
Financial certification
and disclosure

1.9.1

Request for waiver of


pediatric studies

1.9.2

Request for deferral of


pediatric studies

As needed

Use appropriate
sections

1.11.1

Quality information
amendment (only for
information not
covered under Module
3)

As needed

Use appropriate
sections

1.11.2

Safety information
amendment (only for
information not
covered under Module
4)

314.50(g)(1)

314.50(g)(1)
314.50(h)
314.53(b)
314.50(i)
314.52(b)
314.50(j)
314.50(k)
PREA
PREA
314.60
314.60

314.60
314.60

20

Cross reference to other


applications and
information previously
submitted in paper
Statement of right of
reference
Patent Information
(Form FDA 3542a and
FDA form 3542)
Patent certifications

Comprehensive Table of Contents Headings and Hierarchy

314.60

Amendment to an
unapproved
application: Clinical
314.60
Amendment to an
unapproved
application: Clinical
(information not
covered under Module
5)
314.65
Withdrawal of an
unapproved application
314.70 and
Supplements and other
314.71
changes to approved
applications
314.72
Change of ownership
of an application
314.80(2)(ii)(a) Periodic adverse drug
314.80(2)(ii)(c) experience narrative
summary and history of
actions
314.81(b)(1)
Field alert reports
314.81(b)(2)
Annual report
transmittal: FDA form
2252
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary

As needed

Use appropriate
sections

1.11.3

Efficacy information
amendment (only for
information not
covered under Module
5

1.5.5

Withdrawal of an
unapproved application
Use the appropriate
sections

1, 2, 3,
4, 5

As needed

1.3.1.4

5.3.6

1
1

1.12.16
1.1.4

1.13.1

1.13.2

1.13.3

1.13.4

1.13.5

1.13.6

314.81(b)(2)(i)

Annual Report:
Summary

1.13.7

314.81(b)(2)(ii)

Annual Report:
Distribution data
Annual Report:
Labeling
Annual Report:
Chemistry,

1.13.11

1.14

As needed

314.81(b)(2)(iii)
314.81(b)(2)(iv)

21

Change in ownership of
an application
Postmarketing periodic
adverse event drug
experience report
description
Field alert reports
Annual Report
Transmittal: FDA form
2252
Summary of
nonclinical changes
Summary of clinical
pharmacology changes
Summary of safety
changes
Summary of labeling
changes
Summary of
manufacturing changes
Summary of
microbiological
changes
Summary of other
significant new
information
Distribution data
Use appropriate
sections
Use appropriate
sections

Comprehensive Table of Contents Headings and Hierarchy

314.81(b)(2)(v)
314.81(b)(2)(vi)
314.81(b)(2)(vii)

314.81(b)(2)(viii
)

314.81(b)(2)(ix)
314.81(b)(3)(i)
314.81(b)(3)(i)

314.90
314.102
314.102
314.102
314.103(c)
314.103(c)
314.150(c)
314.150(b)
314.420(a)
314.420(b)

manufacturing and
controls
Annual Report:
Nonclinical laboratory
studies
Annual Report:
Clinical data
Annual Report: Status
report of clinical and
nonclinical toxicology
postmarketing study
commitments
Status report of other
(chemistry,
manufacturing,
controls) postmarketing
study commitments
Annual Report: Log of
outstanding regulatory
business
Advertising and
promotional labeling
Transmittal of
Advertisements and
Promotional Labeling
Waivers
Communications:
Meetings
Communications:
Meetings
Communications:
Meetings
Scientific and medical
disputes
Scientific and medical
disputes
Request for withdrawal
of approval
Withdrawal or
suspension of approval
by the FDA
Drug master files
Incorporating DMF
information by
22

As needed

Use appropriate
sections

As needed

1.13.12

1.13.13

Use appropriate
sections
Status report of
clinical and nonclinical
toxicology
postmarketing study
commitments
Status of other
postmarketing study
commitments

1.13.14

Log of outstanding
regulatory business

1.15

Promotional material

1.1.5

1
1

1.12.5
1.6.1

Advertisements and
promotional labeling
transmittal: FDA form
2253
Request for a waiver
Meeting request

1.6.2

1.6.3

1.10.1

1.10.2

1.5.7

1.5.7

1, 2, 3,
4, 5
1

As Needed
1.4.1

Meeting background
materials
Correspondence
regarding meetings
Request for dispute
resolution
Correspondence related
to dispute resolution
Request for withdrawal
of application approval
Other correspondence
regarding status of
application or product
Use appropriate
sections
Letter of Authorization

Comprehensive Table of Contents Headings and Hierarchy

314.420(d)
314.550
314.640

reference
List of authorized
persons to incorporate
by reference
Subpart H: Promotional
materials
Subpart I: Promotional
materials

ANDA
CFR Citation/Source
NUMBER
TITLE
314.94(a)(1)
Application form
GDEA

314.94(a)(4)

Debarment
Certification
Table of Contents
Basis for abbreviated
new drug application
submission
Conditions for use

314.94(a)(5)
314.94(a)(6)

314.94(a)(2)
314.94(a)(3)

1.4.3

1.15

List of authorized
persons to incorporate
by reference
Promotional material

1.15

Promotional material

Module
1
1
N/A
1

CTD /*STF Heading


NUMBER
TITLE
1.2
Application form: FDA
form 356h
1.3.3
Debarment
Certification
N/A
N/A
1.11.11
Basis for submission
statement

1.11.11

Active ingredient

1.11.12

1.11.12

314.94(a)(7)

Route of
administration, dosage
form and strength
Bioequilvance

5.3

314.94(8)(i)

Listed drug labeling

1.14.3.2

314.94(8)(ii)

Copies of proposed
labeling
Statement of proposed
labeling
Comparison of
approved and proposed
labeling
Chemistry,
manufacturing and
control
Reference to
information previously
submitted by sponsor
Patent certification
Notice of certification

1.14

1.14.3.1

1.14.3.1

As needed

Use appropriate
sections

1.4.4

Cross reference to other


applications

1
1

1.3.5.2
1.3.5.3

Patent certification
Certification of non-

314.94(8)(iii)
314.94(8)(iv)
314.94(9)
314.94(11)
314.94(12)
314.95

23

Basis for submission


statement
Comparison of generic
drug and reference
listed drug
Comparison of generic
drug and reference
listed drug
Use appropriate
sections
Approved labeling text
for listed drug
Use appropriate
sections
Annotated comparison
with listed drug
Annotated comparison
with listed drug

Comprehensive Table of Contents Headings and Hierarchy

314.94(13)
314.96
314.96

314.96
314.96

314.102
314.102
314.102
314.103(c)
314.103(c)
314.150(c)
314.150(b)
314.151
314.420(a)
314.420(b)
314.420(d)

of non-validity or noninfringement of patent


Financial certification
and disclosure
Amendment to an
unapproved
application: Chemistry
Amendment to an
unapproved
application: Chemistry
(information not fitting
under module 3)
Amendment to an
unapproved
application: Clinical
Amendment to an
unapproved
application: Clinical
(information not fitting
under module 5)
Communications:
meetings
Communications:
meetings
Communications:
meetings
Scientific and medical
disputes
Scientific and medical
disputes
Request for withdrawal
of approval
Withdrawal or
suspension of approval
by the FDA
Drug master files
Incorporating DMF
information by
reference
List of authorized
persons to incorporate
by reference

24

validity or noninfringement of patent


Financial certification
and disclosure
Use appropriate
sections

1.3.4

As needed

1.11.1

Quality information
amendment

As needed

Use appropriate
sections

1.11.3

Efficacy information
amendment

1.6.1

Meeting request

1.6.2

1.6.3

1.10.1

1.10.2

1.5.7

1.5.7

Meeting background
materials
Correspondence
regarding meetings
Request for dispute
resolution
Correspondence related
to dispute resolution
Request for withdrawal
of an application
Other correspondence
regarding status of
application or product
Use appropriate
sections
Letter of Authorization

1, 2, 3,
4, 5
1
1

As needed
1.4.1
1.4.3

List of authorized
persons to incorporate
by reference

SECTION 7

Conformance Review Checklist


for NDAs

This document provides a checklist for:


o General issues.
o Organization of folders.
o Organization of the electronic submission.

Electronic Document Room

Conformance
Review Checklist
For NDAs

Appl_Type Appl_No

Drug_Name

Sponsor_Applicant

U.S. Department of Health and Human Services


Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

January 1999
TABLE OF CONTENTS

I.

INTRODUCTION................................................................................................... 3

II.

GENERAL ISSUES ................................................................................................ 3


A.
B.
C.
D.
E.
F.
G.

REFUSE TO FILE .................................................................................................... 3


THE ARCHIVAL COPY ........................................................................................... 3
PROVIDING A REVIEW COPY ................................................................................. 3
THE FIELD COPY .................................................................................................. 3
SUPPLEMENTS AND AMENDMENTS ........................................................................ 3
ELECTRONIC SIGNATURES .................................................................................... 3
REVIEW AIDS ....................................................................................................... 3

III. ORGANIZING THE MAIN FOLDER .................................................................... 3


A.
B.
C.
D.
E.

FOLDERS .............................................................................................................. 3
COVER LETTER..................................................................................................... 3
356H FORM .......................................................................................................... 4
NDA TABLE OF CONTENTS .................................................................................. 4
FIGURE OF MAIN FOLDER ..................................................................................... 4

IV. ORGANIZING THE ELECTRONIC SUBMISSION .............................................. 5


A.
B.
C.
D.
E.
F.
G.
H.
I.
J.
K.
L.
M.
N.
O.
P.
Q.
R.
S.

ITEM 1: TABLE OF CONTENTS (INDEX) ................................................................. 5


ITEM 2: LABELING ............................................................................................... 6
ITEM 3: SUMMARY .............................................................................................. 7
ITEM 4: CHEMISTRY, MANUFACTURING, AND CONTROL (CMC) ........................... 7
ITEM 5: NONCLINICAL PHARMACOLOGY AND TOXICOLOGY ................................... 8
ITEM 6: HUMAN PHARMACOLOGY AND BIOAVAILABILITY/BIOEQUIVALENCE ........ 9
ITEM 7: CLINICAL MICROBIOLOGY ..................................................................... 10
ITEM 8: CLINICAL .............................................................................................. 10
ITEM 9: SAFETY UPDATE ................................................................................... 11
ITEM 10: STATISTICAL ....................................................................................... 11
ITEM 11: CASE REPORT TABULATIONS (CRTS) .................................................. 11
ITEM 12: CASE REPORT FORMS .......................................................................... 13
ITEM 13: PATENT INFORMATION ........................................................................ 14
ITEM 14: PATENT CERTIFICATION ...................................................................... 15
ITEM 15: ESTABLISHMENT DESCRIPTION (CBER ONLY) ..................................... 15
ITEM 16: DEBARMENT CERTIFICATION ............................................................... 15
ITEM 17: FIELD COPY CERTIFICATION ................................................................ 15
ITEM 18: USER FEE COVER SHEET...................................................................... 15
ITEM 19: OTHER ................................................................................................ 16

Electronic Document Room


Conformance Review Checklist
I.
II.

INTRODUCTION
GENERAL ISSUES
A.
Refuse to File
B.
The Archival Copy
If portions of the NDA archival copy are submitted in paper and electronic
format, the index (commonly referred to as the table of contents) for the
submission must include the location of the paper documents by volume number
and electronic files by file and folder name(s) so the index is comprehensive.
C.
Providing a Review Copy
D.
The Field Copy
E.
Supplements and Amendments
F.
Electronic Signatures
Until those procedures are in place, documents for which regulations require an
original signature, such as certifications, must be accompanied by a paper copy
that includes the handwritten signature and the NDA number.
G.
Review Aids
Provide all review aid files on floppy disks or CDROMs and secure them in a
standard binder marked clearly on the outside REVIEW AIDS NOT FOR
ARCHIVE. Include the review aids in the appropriate technical section of the
review copy.

III.

ORGANIZING THE MAIN FOLDER

All documents and datasets for the electronic archival copy should be placed in a main
folder using the NDA number (e.g., N123456) as the folder name.
A.
Folders
Inside the main folder, all of the documents and datasets should be organized by
the NDA items described on page 2 of FDA form 356h.
B.
Cover Letter
You should provide a cover letter as a PDF file named cover.pdf inside the main
folder. The cover letter should include the following:

Description of the submission including appropriate regulatory


information.

Description of which portions of the submission are presented only


in paper, only in electronic format, or in both paper and electronic
format.

Description of the electronic submission including the type and number of


electronic media used (e.g., three CDROMs), and the approximate size of the
submission (e.g., 2 gigabytes). Include the format used for DLT tapes.
Statement that the submission is virus free with a description of the software
(name, version, and company) used to check the files for viruses.
The points of contact for the application.

Items Of An NDA As Described In Form 356h


Item Description
1
Table of contents (Index)
2
Labeling
3
Summary
4
Chemistry section
5
Nonclinical pharmacology and toxicology section
6
Human pharmacology and
bioavailability/bioequivalence section
7
Clinical microbiology section
8
Clinical section
9
Safety update report
10
Statistical section
11
Case report tabulations
12
Case report forms
13
Patent information
14
Patent certification
15
Establishment description
16
Debarment certification
17
Field copy certification
18
User fee cover sheet
19
Other

Folder name
main folder
labeling
summary
cmc
pharmtox
hpbio
micro
clinstat
update
clinstat
crt
crf
other
other
other
other
other
other
other

C.
356h Form
You should provide FDA form 356h as a PDF file named 356h.pdf inside the main
folder. On page 2 of the form, you should note next to each item if the documents for the
item are in paper format, electronic format, or both paper and electronic format.
D.
NDA Table Of Contents
Inside the main folder, the applicant should provide a table of contents for the submission
named ndatoc.pdf. See item 1 below for additional information.
E.
Figure of Main Folder
The following is an example of the contents of the main folder for NDA 123456.

772

IV.

ORGANIZING THE ELECTRONIC SUBMISSION


A.
Item 1: Table of Contents (Index)
Regulations at 314.50(b) require a "comprehensive index by volume number and page
number.". For electronic submissions, the comprehensive table of contents contains
three levels of detail and the appropriate hypertext links and bookmarks.
The first level of detail simply lists the items in the NDA as shown on page 2 of FDA
form 356h. This level of the comprehensive table of contents should be a single page and
should be provided as a single PDF file. The file containing the table of contents for the
original NDA should be named ndatoc.pdf. The file containing the table of contents for
an amendment should be named amendtoc.pdf. The file containing the table of contents
for a supplement should be named suppltoc.pdf.
The second level of detail contains the table of contents for each item (e.g., labeling, CMC,
CRTs; see specific item for details). Provide the appropriate bookmarks and hyperlinks for
each document or dataset listed to the appropriate file.
The third level of detail is the table of contents for each document or dataset. For each
document, provide bookmarks for each entry in the document's table of contents to the
appropriate location. For datasets, provide a data definition table as a key to the elements
being used in the datasets.
A hypertext link should be provided from the first-level table of contents to the
corresponding tables of contents for each item. These links are essential for establishing
a comprehensive table of contents for the electronic submission.
Some items, such as item 3 (the submission summary) and items 13 to 18, are single
documents and do not have their own table of contents. In such cases, the hypertext link
from the first level table of contents should go directly to the document.

Example: Table Of Contents For NDA 123456 (n/a = not available)


Item Description
Paper archive copy
Electronic archive
volume number
copy folder
1
2
3
4
5

Table of contents (Index)


Labeling
Summary
Chemistry
Nonclinical pharmacology and
toxicology
Human pharmacokinetics and
bioavailability/bioequivalence
Clinical microbiology
Clinical
Safety update report
Statistical
Case report tabulations
Case report forms
Patent information
Patent certification
Establishment description
Debarment certification
Field copy certification
User fee cover sheet
Other

6
7
8
9
10
11
12
13
14
15
16
17
18
19

B.

1
n/a
n/a
1-4
5-10

main folder
Labeling
Summary
n/a
Pharmtox

n/a

Hpbio

n/a
n/a
n/a
n/a
n/a
n/a
n/a
1
n/a
1
1
1
n/a

Micro
Clinstat
n/a
Clinstat
Crt
Crf
Other
Other
n/a
Other
Other
Other
Other

Item 2: Labeling
1.
Folder
You should place all documents for this item in a single folder named labeling.

2.
Table of contents
3.
Labeling history
4.
Labeling text
Document Information fields should contain the following information: (use only
lower case letters).

Title: brand name


Subject: generic name
Author: applicant, applicant's label code
Keywords: NDA number (in form of 123456), approval status (draft,
approved, cbe for changes being effected or annual for annual report),
date of labeling in the form of ddmmmyyyy. For draft, changes being
effected, and annual report changes, use the date of submission. For
approved labeling, use the date of approval.
An example of the Document Information field for draft labeling text is provided
below. Each item of the keyword field should be separated by a comma.

C.

D.

5.
Package insert
6.
Carton labeling
7.
Container labeling
8.
Other
Item 3: Summary
1.
Folder
2.
Table of contents
3.
Summary document
4.
Bookmarks and hypertext linking
Item 4: Chemistry, Manufacturing, and Control (CMC)
1.
Folders

2.
Table of contents
You must provide a table of contents listing all files provided in the CMC item as
a PDF file named cmctoc.pdf. This table of contents is considered part of the
comprehensive table of contents required in 314.50(b).
7

3.
Drug substance
4.
Drug product
5.
Investigational formulations
6.
Environmental assessment
7.
Methods validation
8.
Batch records
9.
Publications
10.
Bookmarks and hypertext links
For all documents with a table of contents, you must provide bookmarks for each
item in the documents table of contents including all tables, figures, publications,
and appendices. These bookmarks serve as part of the comprehensive table of
contents for the submission and, therefore, are required under 314.50(b).
11.
Full text index
An index of the full text and the Document Information fields of all documents in
this section should be provided. Name the index definition file cmcindex.pdx.
Place all associated index files in a folder named cmcindex. Place the
cmcindex.pdx definition file and the cmcindex subfolder in the main cmc folder.
Associate the cmctoc.pdf file with the index file so that whenever the table of
contents file is opened, the associated index is automatically added to the
available index list.
E.

Item 5: Nonclinical Pharmacology and Toxicology


1.
Folders

2.
Table of contents
You must provide a table of contents listing all study reports (including study
report numbers), publications, and the summary provided in the pharmtox section
as a PDF file named pharmtoc.pdf. If datasets are provided for a study, you
should note this in the table of contents. This table of contents is considered part
of the comprehensive table of contents required in 314.50(b).
3.
Summary document
4.
Study reports

Because files 50 MB or larger are technically more difficult to handle, study


reports that are larger than 50 MB should be divided into two PDF files with the
individual animal line listings for the study provided as a separate file.
5.
Publications
6.
Bookmarks and hypertext links
For all documents with a table of contents, you must provide bookmarks for each
item in the documents table of contents including all tables, figures, publication,
and appendices including datasets, if applicable. If datasets are provided with the
study, you should include a bookmark to the appropriate data definition file
(define.pdf). These bookmarks and hypertext links serve as part of the
comprehensive table of contents for the submission and, therefore, are required
under 314.50(b).
7.
Full text index
8.
Animal line listings as datasets
a.
Format of the datasets
You should provide each dataset as a SAS transport file. Dataset files should be
organized so their size is less than 25 MB per file. The files should not be
compressed. Each dataset should be saved as an individual file.
b.
Organization of data
All datasets for an individual study should be placed in a folder identified by the
study name and all these dataset folders placed in a single folder called datasets.
The datasets folder should be placed in the pharmtox folder.
c.
Documentation of the datasets
d.
Dataset table of contents
e.
General considerations for datasets
F.
Item 6: Human Pharmacology and Bioavailability/Bioequivalence
1.
Folders
2.
Table of contents
You must provide a table of contents listing all study reports (including study report
numbers), publications, and the summaries provided for the hpbio section as a PDF file
named hpbiotoc.pdf and place it in the hpbio folder. If datasets are provided for a study,
you should note this in the table of contents. This table of contents is considered part of
the comprehensive table of contents required in 314.50(b

3.

Summary

G.

4.
Study reports
5.
Datasets
6.
Publications
7.
Bookmarks and hypertext links
For all documents with a table of contents, you must provide bookmarks for each
item in the documents table of contents including all tables, figures, publications,
and appendices including datasets, if applicable. These bookmarks serve as part
of the comprehensive table of contents for the submission and, therefore, are
required under 314.50(b). If datasets are provided with the study, you should
include a bookmark to the appropriate data definition file (define.pdf).
8.
Full text index
Item 7: Clinical Microbiology
1.
Folders

2.
Table of contents
You must provide a table of contents listing all reports and publications for this
section as a PDF file named microtoc.pdf. If datasets are provided for a study,
you should note this in the table of contents. Place this file in the micro folder.
This table of contents is considered part of the comprehensive table of contents
(314.50(b)).
3.
Summary document
4.
Study reports
5.
Datasets
6.
Publications
7.
Bookmarks and hypertext links
As part of a comprehensive table of contents for the submission, you must provide
bookmarks for each item in the documents table of contents including all tables,
figures, and appendices including datasets, if applicable (314.125(b)). If datasets
are provided with a report, you should include a bookmark to the appropriate data
definition file (define.pdf).
8.
Full text index:
H.

Item 8: Clinical
1.
Folders

10

778

I.

J.
K.

2.
Table of contents
You must provide a table of contents listing all files in this section. Provide the
table of contents as a PDF file; name this file clintoc.pdf and place it in the
clinstat folder. We consider the table of contents to be part of the comprehensive
table of contents (314.50(b)).
3.
Study reports
Because files 50 MB or larger are technically more difficult to handle, study
reports that are larger than 50 MB should be divided into two PDF files.
4.
Integrated summaries
5.
Publications
6.
Bookmarks and hypertext links
For all documents with a table of contents, you must provide bookmarks for each
item in the documents table of contents including all tables, figures, publications,
and appendices including datasets. For datasets, you should include a bookmark
to the appropriate data definition file (define.pdf). These bookmarks serve as part
of the comprehensive table of contents for the submission and, therefore, are
required under 314.50(b).
7.
Full text index
Item 9: Safety Update
1.
Folders
All documents for this section should be placed in a single folder named update
and a single PDF file provided for each document.
2.
Table of contents
A table of contents for all files in this section must be provided in the form of a
PDF file as part of the comprehensive table of contents (314.125(b)). The
organization of the table of contents should follow the guidance provided in item
8. Name the PDF file updattoc.pdf and place it in the update folder.
3.
Full text index
Item 10: Statistical For electronic submissions, item 8 and item 10 are identical.
Item 11: Case Report Tabulations (CRTs)
CRTs are item 11 on page 2 of FDA form 356h.

You should provide CRTs in datasets allowing the reviewers to use their own software
for analysis. Each dataset is a single file and, in general, includes a combination of raw
and derived data.

11

In addition to electronic datasets, study data collected for individual patients, organized
by time, can be provided in PDF files. We call this collection of data a patient profile,
and it serves as an adjunct to the electronic datasets. Patient profiles are not meant to be
a replacement for electronic datasets.
1.
Format of the datasets
You should provide each dataset as a SAS transport file as described in the
companion guidance, Regulatory Submissions in Electronic Format General
Considerations (January 1999
Dataset files should be organized so that their size is generally less than 25 MB
per file. The files should not be compressed. Each dataset should be saved as an
individual file.
The data variable names should be no more than 8 characters in length because of
restrictions in our data format. We recommend that you provide a more
descriptive data variable label, up to 32 characters in length.
2.
Organization of data
3.
Documentation of the datasets
You should include two PDF files, one of the data definition tables (define.pdf)
and one of the annotated case report forms (blankcrf.pdf) to describe the datasets
for each study, specific data analysis (e.g., population PK), and integrated
summaries.
4.
Dataset table of contents
The dataset table of contents is also part of the comprehensive table of contents
and must list all studies and integrated summaries that have datasets. You must
provide a hypertext link to the appropriate data definition table file (314.50(b)).
The table of contents should be provided as a PDF file named datatoc.pdf and
placed in the datasets folder.
5.
Full text index
6.
General considerations for datasets
7.
Patient profiles as PDF files
a.
Folders
b.
Table of contents
You must provide in a PDF file a table of contents listing all patient profiles by
study. Name this file protoc.pdf. This table of contents is considered part of the
comprehensive table of contents (314.50(b)). List the patient identification
numbers by study, site, and treatment assignment and describe the location of the
patient profile with the file name and folder(s). Provide a hypertext link between
the documents listed in the table of contents and the corresponding PDF file and
bookmarks for each item in the table of contents. Place the protoc.pdf file in the
profile folder.
c.
Patient profiles
You should provide each individual patients complete patient profile as a single
PDF file. Including the patient ID in the file name will help identify the file.

12

d.
e.

Bookmarks and hypertext links


Full text index

L.
Item 12: Case Report Forms
If a paper CRF was used in the clinical trial, the electronically submitted CRF should be
an exact image or series of images of the paper CRF that contains all original entries with
all modifications, addenda, corrections, comments, annotations, and any extemporaneous
additions. For data collected electronically, all data collected for an individual patient
should be organized by domain and time and provided as a PDF file. This presentation is
the same as a patient profile described in item 11 (CRTs). This file should subsequently
be handled the same as an imaged CRFs.
1.
Folders - You should create a folder for each study to organize the CRFs.
2.
Table of contents
You must provide a table of contents listing all case report forms provided by
study, site and treatment assignment as a PDF file. Name this file crftoc.pdf.
This table of contents is considered part of the comprehensive table of contents
(314.50(b)). List the patient identification numbers by study, site and treatment
assignment and describe the location of the case report forms with the file name
and folder(s). Provide a hypertext link between the documents listed in the table
of contents and the corresponding PDF file and bookmarks for each item in the
table of contents. Place the crftoc.pdf file in the crf folder.
3.
Case report forms
You should provide each individual patients complete CRF as a single PDF file.
Including the patient ID in the file name will help identify the file. Place the PDF
files in the appropriate study site folder. For example, all CRFs for site 001 for

13

study 101 would be placed into a folder named 001, which then would be placed
in a folder named 101.
The Document Information Title field for each file should include the letters crf,
the study number, the site identification, and the patients unique ID number. The
unique patient ID number should be composed of elements of the study number,
site number, and patient number, or a functional equivalent. For example, the
CRF for patient 001 in study 2001 at site 003 would have the following in the
Title field: crf, study 2001, site 003, PID 2001-003-001.
4.
Bookmarks and hypertext links
Each CRF must have bookmarks as part of the comprehensive table of contents
required under 314.50(b).
5.
Full text index
An index of the full text and the Document Information field of all documents in
the crf folder should be provided. Even if all of the CRFs are images, the text in
the Document Information field should be indexed. The index definition file
should be named crfindex.pdx. Place all associated index files in a folder named
crfindex. Place the crfindex.pdx definition file and the crfindex subfolder in the
main crf folder. Associate crftoc.pdf with the index file so that whenever the
table of contents file is opened, the associated index is automatically added to the
available index list.
M.

Item 13: Patent Information


1.
Folder
You should place documents for this section in the folder named other.
2.
Table of contents

14

N.

O.

There should be a hypertext link from the submission table of contents directly to
the patinfo.pdf file.
3.
Patent information
You should provide the information pertaining to the patent information in a
single PDF file named patinfo.pdf.
Item 14: Patent Certification
1.
Folder
You should place the document for this section in the folder named other.
2.
Table of contents
There should be a hypertext link from the submission table of contents directly to
the patcert.pdf file.
3.
Patent certification
You should provide the information pertaining to the patent certification in a
single PDF file named patcert.pdf.
Item 15: Establishment Description (CBER only)
Item 15 on page 2 of FDA form 356h applies only to submissions to CBER.

P.

Item 16: Debarment Certification


1.
Folder
You should place the debarment certification in the folder named other.
2.
Table of contents
There should be a hypertext link from the submission table of contents directly to
the debar.pdf file.
3.
Debarment certification
The debarment statement should be provided in a single PDF file named
debar.pdf.

Q.

Item 17: Field Copy Certification


1.
Folder
You should place the field copy certification in the folder named other.
2.
Table of contents
There should be a hypertext link from the submission table of contents directly to
the fieldcer.pdf file.
3.
Field copy certification
The field copy certification should be provided in a single PDF file named
fieldcer.pdf .

R.

Item 18: User Fee Cover Sheet


1.
Folder
You should place the User Fee Cover Sheet in the folder named other.
2.
Table of contents
There should be a hypertext link from the submission table of contents directly to
the userfee.pdf file.
3.
User fee cover sheet (FDA form 3397)

15

S.

The user fee cover sheet should be provided as a single PDF file named
userfee.pdf.
Item 19: Other
1.
Folder
You should place all additional information for this item in the folder named
other.
2.
Table of contents
There should be a hypertext link from the submission table of contents directly to
each file in this item.
3.
Other items
You should provide each additional item as a separate PDF file

16

SECTION 8

eCTD Backbone Files


Specifications for Module 1

This document provides specifications for creating the eCTD backbone file
for Module 1 for use with the guidance to industry: Providing Regulatory
Submissions in Electronic Format Human Pharmaceutical Applications
and Related Submissions.

The eCTD Backbone Files Specification for Module 1

The eCTD BACKBONE FILES SPECIFICATION FOR MODULE 1


Revision History
Date
Version
2003-08-13
1.0
2004-03-01
1.1
2006-04-13
1.2
2006-12-13
1.3

Summary of Changes

Original version
Clarifications to the original version
Change to Related Sequence Example
Change to XML coding for a supplement to an original application
related sequence example

The eCTD Backbone Files Specification for Module 1

TABLE OF CONTENTS
I.

START OF
II.

THE MODULE 1 ECTD BACKBONE FILE.............................................................................3

ADMIN ELEMENTS ........................................................................................................................................4


A.

APPLICANT-INFO ELEMENT ..............................................................................................................................4


Company-name Element.............................................................................................................................4
Date-of-submission Element.......................................................................................................................4
B. PRODUCT-DESCRIPTION ELEMENT ...................................................................................................................5
1.
Application-number Element......................................................................................................................5
2.
Prod-name Element ....................................................................................................................................5
C. APPLICATION-INFORMATION ELEMENT ............................................................................................................6
1.
Submission Element....................................................................................................................................6
1.
2.

III. LEAF ELEMENT ..............................................................................................................................................8


IV.

HEADING ELEMENTS FOR MODULE 1 ....................................................................................................9


1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.

V.

Forms..........................................................................................................................................................9
Cover Letters ............................................................................................................................................10
Administrative Information.......................................................................................................................10
Reference Section .....................................................................................................................................11
Application Status Documentation ...........................................................................................................12
Meetings ...................................................................................................................................................13
Fast Track.................................................................................................................................................13
Special Protocol Assessment Request.......................................................................................................14
Pediatric Administrative Information.......................................................................................................14
Dispute Resolution....................................................................................................................................15
Information Not Covered Under Modules 2 to 5 ......................................................................................15
Other Correspondence .............................................................................................................................16
Annual Report...........................................................................................................................................18
Labeling....................................................................................................................................................20
Promotional Material ...............................................................................................................................23
Risk Management Plans ...........................................................................................................................23

DOCUMENT TYPE DEFINITION (DTD) ...................................................................................................23

The eCTD Backbone Files Specification for Module 1

The eCTD Backbone Files Specification for Module 1


(Module 1 eCTD Backbone File)
This document provides specifications for creating the electronic common technical document
(eCTD) backbone file for Modules 1 for use with the guidance to industry: Providing Regulatory
Submissions in Electronic Format Human Pharmaceutical Applications and Related
Submissions.
The Module 1 eCTD Backbone File includes information for each file submitted in Module 1.
The file information is provided within an XML element called the leaf element. The leaf
elements are organized using the Module1 headings. The Module 1 headings are named and
organized according to the subject matter of the information contained in the file. The heading
information is provided as an XML element called header in this specification. In addition, the
Module 1 eCTD Backbone File includes administrative information about each submission. The
administrative information is provided in the admin element.
Because the Module 1 eCTD Backbone File may be used in a wide range of applications and
related submission types, a specific submission may not use all of the possible headings
elements. You should include the header needed to organize the files in your submission.
I. START OF THE MODULE 1 ECTD BACKBONE FILE
You should name the module 1eCTD Backbone File us-regional.xml and place it in the us folder
that is in the folder named m1 as described in Providing Regulatory Submissions in Electronic
Format Human Pharmaceutical Applications and Related Submissions. For example, the path
for the us-regional.xml file for sequence number 0006 is 0006/m1/us/us-regional.xml. You
should place a leaf element in the Module 2 to 5 eCTD Backbone File for the us-regional.xml
file. In the corresponding Module 2 to 5 eCTD Backbone File, the operation attribute should
have a value of new.
The header of the Module 1 eCTD Backbone File is always the same. It contains machinereadable information about the following:

Version of XML being used


Type of characters that are allowed in the file
Location of the standards that control the organization of the file

A sample of the common elements is provided:


<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE fda-regional:fda-regional SYSTEM "../../util/us-regional.dtd">
< fda-regional:fda-regional
xmlns:ectd="http://www.ich.org/ectd"
xmlns:xlink="hyyp://www.w3c.org/1999/xlink">
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The eCTD Backbone Files Specification for Module 1


<!--All the heading elements and content for module 1 should be
provided after these elements and before the last element closing
tag named </fda-regional:fda-regional> -->
</fda-regional:fda-regional>
The elements used to organize files for Module1 are placed within the area represented by the
comment in the example shown above. Information about creating those elements is provided in
other sections of this specification.
II. ADMIN ELEMENTS
Administrative information is contained in the admin element which is contained in the fdaregional:fda-regional element1. There are three elements contained in the element named
admin:. applicant-info, product-description, and application-information. These elements should
be placed in the order as they are listed above.
<fda-regional:fda-regional>
<admin>
<applicant-info>
</applicant-info>
<product-description>
</product-description>
<applicant-information>
</applicant-information>
</admin>
</fda-regional:fda-regional>
.

Applicant-info Element

The application-info elements contains the applicant-info element: company-name, and date-ofsubmission.
0. Company-name Element
The sponsor or applicants name is in the company-name element. An example of the companyname element for the VeryBest Drug Company with its content is provided:
<company-name>VeryBest Drug Company</company-name>
You should provide this element with every submission.
0. Date-of-submission Element
1

Both the start tag and the end tag of the admin element should be placed between the start and end tags of the:fdaregional element.
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The eCTD Backbone Files Specification for Module 1


An element named date is contained in the date-of-submission element. You should place the
date of submission in the date element. This is sometimes referred to as the "letter date" because
it can be the same as the date on the cover letter. Provide an attribute for the date element named
format. The format has a fixed value of "yyyymmdd" and indicates the content of the date
element is the four-digit year followed by two-digit month followed by two-digit day.
An example of the date-of-submission element with its content is provided:
<date-of-submission>
<date format="yyyymmdd">20020208</date>
</date-of-submission >
You should provide this element with every submission.
.

Product-description Element

There are two elements contained in the product-description element: application-number, and
prod-name.
0. Application-number Element
The 6 digit application number in placed in the application-number element. You should
provide only the digits, including any leading zeros for the application number without letters or
dashes. An example of the application-number element for NDA 99-999 with its content is
provided:
<application-number>099999</application-number >
You should provide this element with every sequence number submission to the application.
0. Prod-name Element
The prod-name elements contains up to four different types of product name, all of which can
occur in a single submission. Provide an attribute for the prod-name element named type.
Indicate the type of product name you contained in the prod-name element by choosing one of
the four allowed values. The table below lists the available product name types (type attribute
values) with their meaning:
type Attribute and Value
type="established"
type="proprietary"
type="chemical"
type="code"

Version 1.3

Product Name Type


Established name (e.g., proper name)
Proprietary name (e.g., brand name, trade name)
Chemical name. (spell Greek characters and don't use
superscript or subscript)
Internal code used by the application sponsor.

The eCTD Backbone Files Specification for Module 1


There is no limit to the number of prod-name elements. An example of prod-name elements
with their type attribute values and content is provided:
<prod-name type="proprietary">Cure All</prod-name >
<prod-name type="established">Cures</prod-name >
<prod-name type="chemical">H2O</prod-name >
<prod-name type="code">alpha-8</prod-name >
<prod-name type="code">beta-3</prod-name >
You should provide at least one prod-name element with each sequence numbered submission to
the application.
.

Application-information Element

The element application-information contains the submission element. You should provide an
attribute for the application-information element named application-type. Indicate the type of
application for this submission in the application-type element by choosing one of the types
allowed. The table below lists the available application types (application-type attribute values)
with their meaning:
application-type Attribute and Value
application-type="nda"
application-type="anda"
application-type="bla"
application-type="ind"
application-type="dmf"

Application Type
New Drug Application
Abbreviated New Drug Application
Biologics License Application
Investigational new drug application.
Master file

0. Submission Element
There are two elements in the submission element: sequence-number, and related-sequencenumber. You should provide a submission-type attribute for the submission element that contains
the value for the type of submission from the following table:
Submission-type
Attribute Value
original-application"
"amendment"
"resubmission"
"presubmission"
"annual-report"

Version 1.3

Meaning
A complete new application that has never before been submitted
All submissions to pending original submission or pending
supplements to approved applications including responses to
information request letters
A complete response to an action letter, or submission of an
application that has been the subject of a withdrawal or a refusal to
file
Information submitted prior to the submission of a complete new
application
Annual Reports to applications

The eCTD Backbone Files Specification for Module 1


Submission-type
Attribute Value
"establishmentdescription-supplement"
"efficacy-supplement"

"labeling-supplement"
"chemistrymanufacturing-controlssupplement"
"other"

Meaning
Supplements to the information contained in the establishment
description section for biological products
Submissions for such changes as a new indication or dosage regimen
for an approved product, a comparative efficacy claim naming
another product, or a significant alteration in the patient population;
e.g., prescription to Over-The-Counter switch
All label change supplements required under 21 CFR 314.70 and 21
CFR 601.12 that do not qualify as efficacy supplements;
Manufacturing and Controls Supplement manufacturing change
supplement submissions as provided in 21 CFR 314.70, 21 CFR
314.71, 21 CFR 314.72 and 21 CFR 601.12
Not among those listed above

) Sequence-number Element
You should include the sequence number of the submission in the sequence-number element.
The sequence number should be exactly 4 digits with no spaces between them. You should
provide a sequence-number element with every submission. Note that sequence numbers are
used to differentiate between submissions for the same application and do not necessarily
correspond to the order they are received by the Agency. An example of the first application
sequence number element with its content is provided:
<sequence-number>0000</sequence-number>
) Related-sequence-number Element
When providing an amendment to an earlier submission, you should include the sequence
number of the earlier submission in the related-sequence-number element. The sequence
number should be exactly 4 digits with no spaces between them. If this submission is related to
more than one previous submission, you should provide each previous submission's sequence
number in a separate related-sequence-number element. There is no limit to the number of
related-sequence-number elements. The following is an example of the related sequence
number. An application has the following submissions:
0000
0001
0002
0003
0004
0005
0006
0007

- Original application
- an amendment to original application
- an amendment to original application
- a chemistry, manufacturing and control supplement
- an amendment to original application
- an amendment to the supplement
- an amendment to the original application
- an amendment that relates to both the original and supplement

A non-XML representation would relate this as:

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The eCTD Backbone Files Specification for Module 1

Sequence-number
0000
0001
0002
0003
0004
0005
0006
0007

Related-sequence-number***
0000
0000
0000
0003
0000
0000 0003

Example XML coding for the original application would look like:
<submission submission-type="original-application">
<sequence-number>0000</sequence-number>
</submission>
Example XML coding for a supplement to an original application would look like:
<submission submission-type="chemistry-manufacturing-controls-supplement ">
<sequence-number>0003</sequence-number>
</submission>
Example XML coding for a submission element of an amendment that would apply to two or
more original submissions, such as sequence number 0007 above, would look like:
<submission submission-type="chemistry-manufacturing-controls-supplement">
<sequence-number>0007</sequence-number>
<related-sequence-number>0000</related-sequence-number>
<related-sequence-number>0003</related-sequence-number>
</submission>
Example XML coding for an amendment to an original application or original supplement
(example shown is for an amendment to the original application):
<submission submission-type="amendment">
<sequence-number>0002</sequence-number>
<related-sequence-number>0000</related-sequence-number>
</submission>
III. LEAF ELEMENT
Information for an individual document is contained in the leaf element, its attributes and its
"title" element. The leaf element is used repeatedly throughout the eCTD backbone files to
provide individual information for each document being submitted. Detailed descriptions of
each part of the leaf element and how to use them are found in the document The eCTD

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The eCTD Backbone Files Specification for Module 1


Backbone Files Specifications for Modules 2 through 5. When preparing the us-regional.xml file,
the xlink:href and modified-file leaf attributes should reflect the path relative to the location of
the us-regional.xml file location in the submission. The following is an example of a xlink:href
attribute and its value for the 356h.pdf in module 1 in the same submission:
xlink:href="356h.pdf "
The following is a example of a modified-file leaf attribute and its value in module 1 in an earlier
submission:
modified-file="../../../0001/m1/us/us-regional.xml#id34567
IV. HEADING ELEMENTS FOR MODULE 1
This is the equivalent to the heading elements described in the document The eCTD Backbone
Files Specifications for Modules 2 through 5. This section describes the heading elements
relevant to module 1.
The module 1 heading elements are listed in the following table. Both the start tag and end tag
for each heading element are provided. If there are one or more subheadings for the heading, the
corresponding element end tag will occur on the table row below the last relevant subheading.
The leaf element is included to show where the leaf elements should be placed. The details for
the leaf elements are not shown on this table to keep it clearer. The leaf elements should only
occur where indicated in this table. A heading element may contain any number of leaf elements.
If no documents are submitted for a heading, you should omit the element for that heading in the
eCTD backbone file.

Module 1 Heading
Regional information
0. Forms
Choose one of the following elements to contain
your form's leaf element.
)
Investigational New
Drug (IND)
) New Drug Application
(NDA) or New Biologic
Application (BLA)

Version 1.3

Heading element (leaf element abbreviated


for clarity)
<m1-regional>
<m1-1-forms>
<m1-1-1-fda-form-1571>
<leaf>
</leaf>
</m1-1-1-fda-form-1571>
<m1-1-2-fda-form-356h>
<leaf>
</leaf>
</m1-1-2-fda-form-356h>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) User Fee Cover Sheet

) Annual Report
Transmittal
) Advertising and
Promotional Labeling
) Transmittal of Labels
and Circulars

0. Cover Letters

End of Forms

0. Administrative Information
) Applicant Information

<m1-3-1-1-cofa-con>
<leaf>
</leaf>
</m1-3-1-1-cofa-con>
<m1-3-1-2-change-contactagent>
<leaf>
</leaf>
</m1-3-1-2-change-contactagent>
<m1-3-1-3-change-sponsor>
<leaf>
</leaf>
</m1-3-1-3-change-sponsor>
<m1-3-1-4-transfer-obligation>
<leaf>
</leaf>
</m1-3-1-4-transferobligation>

(0) Change of Address

(0) Change of Agent

(0) Sponsor Change

(0) Obligation Transfer

Version 1.3

Heading element (leaf element abbreviated


for clarity)
<m1-1-3-fda-form-3397>
<leaf>
</leaf>
</m1-1-3-fda-form-3397>
<m1-1-4-fda-form-2252>
<leaf>
</leaf>
</m1-1-4-fda-form-2252>
<m1-1-5-fda-form-2253>
<leaf>
</leaf>
</m1-1-5-fda-form-2253>
<m1-1-6-fda-form-2567>
<leaf
</leaf>
</m1-1-6-fda-form-2567>
</m1-1-forms>
<m1-2-cover-letters>
<leaf>
</leaf>
</m1-2-cover-letters>
<m1-3-administrative-information>
<m1-3-1-applicant-information>

10

The eCTD Backbone Files Specification for Module 1


Module 1 Heading

Heading element (leaf element abbreviated


for clarity)
<m1-3-1-5-change-application(0) Ownership Change
ownership>
<leaf>
</leaf>
</m1-3-1-5-changeapplication-ownership>
End Applicant Information
</m1-3-1-applicant-information>
<m1-3-2-field-copy-certification>
) Field Copy Certification
<leaf>
</leaf>
</m1-3-2-field-copy-certification>
<m1-3-3-debarment-certification>
) Debarment Certification
<leaf>
</leaf>
</m1-3-3-debarment-certification>
<m1-3-4-financial-certification) Financial Disclosure
disclosure>
<leaf>
</leaf>
</m1-3-4-financial-certificationdisclosure>
<m1-3-5-patent-exclusivity>
) Patent Exclusivity
(0) Patent Information

(0) Patent Certification

(0) Exclusivity Request

End of Patent Exclusivity


End of Administrative Information
0. Reference Section

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11

<m1-3-5-1-patent-information>
<leaf>
</leaf>
</m1-3-5-1-patentinformation>
<m1-3-5-2-patentcertification>
<leaf>
</leaf>
</m1-3-5-2-patentcertification>
<m1-3-5-3-exclusivityrequest>
<leaf>
</leaf>
</m1-3-5-3-exclusivityrequest>
</m1-3-5-patent-exclusivity>
</m1-3-administrative-information>
<m1-4-references>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Letter of Authorization

) Statement of Right to
Reference

) List of Authorized to
Persons to Incorporate by
Reference

) Cross Reference to
Other Applications

0. Application
Documentation

End References
Status

) Withdrawal Request

) Inactivation Request

) Reactivation Request

) Reinstatement Request

Version 1.3

12

Heading element (leaf element abbreviated


for clarity)
<m1-4-1-letter-authorization>
<leaf>
</leaf>
</m1-4-1-letter-authorization>
<m1-4-2-statement-rightreference>
<leaf>
</leaf>
</m1-4-2-statement-rightreference>
<m1-4-3-list-authorized-personsincorporate-reference>
<leaf>
</leaf>
</m1-4-3-list-authorized-personsincorporate-reference>
<m1-4-4-cross-reference-otherapplications>
<leaf>
</leaf>
</m1-4-4-cross-reference-otherapplications>
</m1-4-references>
<m1-5-application-status>
<m1-5-1-withdrawal-request>
<leaf>
</leaf>
</m1-5-1-withdrawal-request>
<m1-5-2-inactivation-request>
<leaf>
</leaf>
</m1-5-2-inactivation-request>
<m1-5-3-reactivation-request>
<leaf>
</leaf>
</m1-5-3-reactivation-request>
<m1-5-4-reinstatement-request>
<leaf>
</leaf>
</m1-5-4-reinstatement-request>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Withdrawal of
Unapproved NDA

) Withdrawal of Listed
Drug

) Request for Withdrawal


of Application Approval

0. Meetings

End Application Status

) Meeting Request

) Meeting Background
Materials

) Correspondence
Regarding Meetings

0. Fast Track

End Meetings

) Fast Track Designation


Request

Version 1.3

13

Heading element (leaf element abbreviated


for clarity)
<m1-5-5-withdrawal-unapprovednda>
<leaf>
</leaf>
</m1-5-5-withdrawal-unapprovednda>
<m1-5-6-withdrawal-of-listeddrug>
<leaf>
</leaf>
</m1-5-6-withdrawal-of-listeddrug>
<m1-5-7-request-withdrawalapplication-approval>
<leaf>
</leaf>
</m1-5-7-request-withdrawalapplication-approval>
</m1-5-application-status>
<m1-6-meetings>
<m1-6-1-meeting-request>
<leaf>
</leaf>
</m1-6-1-meeting-request>
<m1-6-2-meeting-backgroundmaterials>
<leaf>
</leaf>
</m1-6-2-meeting-backgroundmaterials>
<m1-6-3-correspondenceregarding-meetings>
<leaf>
</leaf>
</m1-6-3-correspondenceregarding-meetings>
</m1-6-meetings>
<m1-7-fast-track>
<m1-7-1-fast-track-designationrequest>
<leaf>
</leaf>
</m1-7-1-fast-track-designationrequest>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Fast Track Designation
Withdrawal Request

) Rolling Review Request

0. Special
Request

End Fast Track


Protocol Assessment

) Clinical Study

) Carcinogenicity Study

) Stability Study

End Special Protocol


0. Pediatric
Information

Administrative

) Request for Waiver of


Pediatric Studies

) Request for Deferral of


Pediatric Studies

Version 1.3

14

Heading element (leaf element abbreviated


for clarity)
<m1-7-2-fast-track-designationwithdrawal-request>
<leaf>
</leaf>
</m1-7-2-fast-track-designationwithdrawal-request>
<m1-7-3-rolling-review-request>
<leaf>
</leaf>
</m1-7-3-rolling-review-request>
</m1-7-fast-track>
<m1-8-special-protocol-assessmentrequest>
<m1-8-1-clinical-study>
<leaf>
</leaf>
<m1-8-1-clinical-study>
<m1-8-2-carcinogenicity-study>
<leaf>
</leaf>
<m1-8-2-carcinogenicity-study>
<m1-8-3-stability-study>
<leaf>
</leaf>
<m1-8-3-stability-study>
</m1-8-special-protocol-assessmentrequest>
<m1-9-pediatric-administrativeinformation>
<m1-9-1-request-waiver-pediatricstudies>
<leaf>
</leaf>
</m1-9-1-request-waiver-pediatricstudies>
<m1-9-2-request-deferralpediatric-studies>
<leaf>
</leaf>
</m1-9-2-request-deferralpediatric-studies>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Request for Pediatric
Exclusivity Determination

) Proposed Pediatric
Study Request and
amendments

) Proposal for Written


Agreement

) Other Correspondence
Regarding Pediatric
Exclusivity or Study Plans

End Pediatric
0. Dispute Resolution
) Request for Dispute
Resolution

) Correspondence Related
to Dispute Resolution

End Dispute Resolution


0. Information Not Covered Under
Modules 2 to 5

Version 1.3

15

Heading element (leaf element abbreviated


for clarity)
<m1-9-3-request-pediatricexclusivity-determination>
<leaf>
</leaf>
</m1-9-3-request-pediatricexclusivity-determination>
<m1-9-4-proposed-pediatric-studyrequest-amendments>
<leaf>
</leaf>
</m1-9-4-proposed-pediatricstudy-request-amendments>
<m1-9-5-proposal-writtenagreement>
<leaf>
</leaf>
</m1-9-5-proposal-writtenagreement>
<m1-9-6-other-correspondenceregarding-pediatric-exclusivitystudy-plans>
<leaf>
</leaf>
</m1-9-6-other-correspondenceregarding-pediatric-exclusivitystudy-plans>
<\m1-9-pediatric-administrativeinformation>
<m1-10-dispute-resolution>
<m1-10-1-request-for-disputeresolution>
<leaf>
</leaf>
</m1-10-1-request-for-disputeresolution>
<m1-10-2-correspondence-relatedto-dispute-resolution>
<leaf>
</leaf>
</m1-10-2-correspondencerelated-to-dispute-resolution>
</m1-10-dispute-resolution>
<m1-11-information-amendment>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Quality Information
Amendment

) Safety Information
Amendment

) Efficacy Information
Amendment

) Multiple Module
Information Amendments

End Modules
0. Other Correspondence
) Pre IND
Correspondence

) Request to Charge

) Notification of Charging
Under Treatment IND

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16

Heading element (leaf element abbreviated


for clarity)
<m1-11-1-quality-informationamendment>
<leaf>
</leaf>
</m1-11-1-quality-informationamendment>
<m1-11-2-safety-informationamendment>
<leaf>
</leaf>
</m1-11-2-safety-informationamendment>
<m1-11-3-efficacy-informationamendment>
<leaf>
</leaf>
</m1-11-3-efficacy-informationamendment>
<m1-11-4-multiple-moduleinformation-amendments>
<leaf>
</leaf>
</m1-11-4-multiple-moduleinformation-amendments>
</m1-11-information-amendment>
<m1-12-other-correspondence>
<m1-12-1-pre-indcorrespondence>
<leaf>
</leaf>
</m1-12-1-pre-indcorrespondence>
<m1-12-2-request-charge>
<leaf>
</leaf>
</m1-12-2-request-charge>
<m1-12-3-notification-chargingunder-treatment-ind>
<leaf>
</leaf>
</m1-12-3-notification-chargingunder-treatment-ind>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Request for Comments
and Advice on an IND

) Request for Waiver

) Exemption from
Informed Consent for
Emergency Research

) Public Disclosure
Statement for Emergency
Care Research

) Correspondence
Regarding Emergency Care
Research

) Notification of
Discontinuation of Clinical
Trial

) Generic Drug
Enforcement Act Statement

Version 1.3

17

Heading element (leaf element abbreviated


for clarity)
<m1-12-4-request-commentsadvice-ind>
<leaf>
</leaf>
</m1-12-4-request-commentsadvice-ind>
<m1-12-5-request-waiver>
<leaf>
</leaf>
</m1-12-5-request-waiver>
<m1-12-6-exemption-informedconsent-emergency-research>
<leaf>
</leaf>
</m1-12-6-exemption-informedconsent-emergency-research>
<m1-12-7-public-disclosurestatement-emergency-careresearch>
<leaf>
</leaf>
</m1-12-7-public-disclosurestatement-emergency-careresearch>
<m1-12-8-correspondenceregarding-emergency-careresearch>
<leaf>
</leaf>
</m1-12-8-correspondenceregarding-emergency-careresearch>
<m1-12-9-notificationdiscontinuation-clinical-trial>
<leaf>
</leaf>
</m1-12-9-notificationdiscontinuation-clinical-trial>
<m1-12-10-generic-drugenforcement-act-statement>
<leaf>
</leaf>
</m1-12-10-generic-drugenforcement-act-statement>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Basis for Submission
Statement

) Comparison of Generic
Drug and Reference Listed
Drug

) Request for Waiver For


In Vivo Studies

) Environmental Analysis

) Request for Waiver of In


Vivo Bioavailability Studies

) Field Alert Reports

End of correspondence
0. Annual Report
) Summary for
Nonclinical Studies

Version 1.3

18

Heading element (leaf element abbreviated


for clarity)
<m1-12-11-basis-submissionstatement>
<leaf>
</leaf>
</m1-12-11-basis-submissionstatement>
<m1-12-12-comparison-genericdrug-reference-listed-drug>
<leaf>
</leaf>
</m1-12-12-comparison-genericdrug-reference-listed-drug>
<m1-12-13-request-waiver-invivo-studies>
<leaf>
</leaf>
</m1-12-13-request-waiver-invivo-studies>
<m1-12-14-environmentalanalysis>
<leaf>
</leaf>
</m1-12-14-environmentalanalysis>
<m1-12-15-request-waiver-invivo-bioavailability-studies>
<leaf>
</leaf>
</m1-12-15-request-waiver-invivo-bioavailability-studies>
<m1-12-16-field-alert-reports>
<leaf>
</leaf>
</m1-12-16-field-alert-reports>
</m1-12-other-correspondence>
<m1-13-annual-report>
<m1-13-1-summary-nonclinicalstudies>
<leaf>
</leaf>
</m1-13-1-summary-nonclinicalstudies>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Summary for Clinical
Pharmacology Information

) Summary of Safety
Information

) Summary of Labeling
Changes

) Summary of
manufacturing changes

) Summary of
microbiological changes

) Summary of Other
Significant New
Information

) Individual Study
Information

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19

Heading element (leaf element abbreviated


for clarity)
<m1-13-2-summary-clinicalpharmacology-information>
<leaf>
</leaf>
</m1-13-2-summary-clinicalpharmacology-information>
<m1-13-3-summary-safetyinformation>
<leaf>
</leaf>
</m1-13-3-summary-safetyinformation>
<m1-13-4-summary-labelingchanges>
<leaf>
</leaf>
</m1-13-4-summary-labelinghanges>
<m1-13-5-summary-ofmanufacturing-changes>
<leaf>
</leaf>
</m1-13-5-summary-ofmanufacturing-changes>
<m1-13-6-summary-ofmicrobiological-changes>
<leaf>
</leaf>
</m1-13-6-summary-ofmicrobiological-changes
<m1-13-7-summary-othersignificant-new-information>
<leaf>
</leaf>
</m1-13-7-summary-othersignificant-new-information>
<m1-13-8-individual-studyinformation>
<leaf>
</leaf>
</m1-13-8-individual-studyinformation>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) General Investigational
Plan

) Foreign Marketing
History

) Distribution Data

) Status of Postmarketing
Study Commitments

) Status of Other
Postmarketing Studies

) Log of Outstanding
Regulatory Business

0. Labeling

End Annual Report

) Draft Labeling

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20

Heading element (leaf element abbreviated


for clarity)
<m1-13-9-general-investigationalplan>
<leaf>
</leaf>
</m1-13-9-general-investigationalplan>
<m1-13-10-foreign-marketinghistory>
<leaf>
</leaf>
</m1-13-10-foreign-marketinghistory>
<m1-13-11-distribution-data>
<leaf>
</leaf>
</m1-13-11-distribution-data>
<m1-13-12-status-postmarketingstudy-commitments>
<leaf>
</leaf>
</m1-13-12-status-postmarketingstudy-commitments>
<m1-13-13-status-otherpostmarketing-studies>
<leaf>
</leaf>
</m1-13-13-status-otherpostmarketing-studies>
<m1-13-14-log-outstandingregulatory-business>
<leaf>
</leaf>
</m1-13-14-log-outstandingregulatory-business>
</m1-13-annual-report>
<m1-14-labeling>
<m1-14-1-draft-labeling>
<leaf>
</leaf>
</m1-14-1-draft-labeling>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
(0) Draft Carton and Container Labels

(0) Annotated Draft Labeling Text

(0) Draft Labeling Text

(0) Label Comprehension Studies

(0) Labeling History

) Final Labeling
(0) Final Carton or Container Labels

(0) Final Package Insert (package


inserts, patient information, medication
guides)

(0) Final labeling Text

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21

Heading element (leaf element abbreviated


for clarity)
<m1-14-1-1-draft-cartoncontainer-labels>
<leaf>
</leaf>
</m1-14-1-1-draft-cartoncontainer-labels>
<m1-14-1-2-annotated-draftlabeling-text>
<leaf>
</leaf>
</m1-14-1-2-annotated-draftlabeling-text>
<m1-14-1-3-draft-labeling-text>
<leaf>
</leaf>
</m1-14-1-3-draft-labeling-text>
<m1-14-1-4-label-comprehensionstudies>
<leaf>
</leaf>
</m1-14-1-4-label-comprehensionstudies>
<m1-14-1-5-labeling-history>
<leaf>
</leaf>
</m1-14-1-5-labeling-history>
<m1-14-2-final-labeling>
</m1-14-2-final-labeling>
<m1-14-2-1-final-carton-containerlabels>
<leaf>
</leaf>
</m1-14-2-1-final-cartoncontainer-labels>
<m1-14-2-2-final-package-insertpackage-inserts>
<leaf>
</leaf>
</m1-14-2-2-final-package-insertpackage-inserts>
<m1-14-2-3-final-labeling-text>
<leaf>
</leaf>
</m1-14-2-3-final-labeling-text>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading
) Listed Drug Labeling

(0) Annotated Comparison with Listed


Drug

(0) Approved Labeling Text for Listed


Drug

(0) Labeling Text for Reference Listed


Drug

) Investigational Drug
Labeling

(0) Investigational Brochure

(0) Investigational Drug Labeling

) Foreign Labeling

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22

Heading element (leaf element abbreviated


for clarity)
<m1-14-3-listed-drug-labeling>
<leaf>
</leaf>
</m1-14-3-listed-drug-labeling>
<m1-14-3-1-annotatedcomparison-listed-drug>
<leaf>
</leaf>
</m1-14-3-1-annotatedcomparison-listed-drug>
<m1-14-3-2-approved-labelingtext-listed-drug>
<leaf>
</leaf>
</m1-14-3-2-approved-labelingtext-listed-drug>
<m1-14-3-3-labeling-textreference-listed-drug>
<leaf>
</leaf>
</m1-14-3-3-labeling-textreference-listed-drug>
<m1-14-4-investigational-druglabeling>
<leaf>
</leaf>
</m1-14-4-investigational-druglabeling>
<m1-14-4-1-investigationalbrochure>
<leaf>
</leaf>
</m1-14-4-1-investigationalbrochure>
<m1-14-4-2-investigational-druglabel>
<leaf>
</leaf>
</m1-14-4-2-investigational-druglabel>
<m1-14-5-foreign-labeling>
<leaf>
</leaf>
</m1-14-5-foreign-labeling>

The eCTD Backbone Files Specification for Module 1


Module 1 Heading

Heading element (leaf element abbreviated


for clarity)
End Labeling
</m1-14-labeling>
0. Promotional Material
<m1-15-promotional-material>
<leaf>
</leaf>
</m1-15-promotional-material>
0. Risk Management Plans
<m1-16-risk-management-plans>
<leaf>
</leaf>
</m1-16-risk-management-plans>
End Regional Leafs </m1-regional>
V. DOCUMENT TYPE DEFINITION (DTD)
<?xml version="1.0" encoding="UTF-8"?>
<!-- ================== DTD INFORMATION ========================== -->
<!-- US-regional DTD Version 2-01 -->
<!-- ================== TOP LEVEL ELEMENTS ======================= -->
<!ENTITY % att " ID
ID #IMPLIED
xml:lang CDATA #IMPLIED">
<!ELEMENT fda-regional:fda-regional (admin, m1-regional?)>
<!ATTLIST fda-regional:fda-regional
xmlns:fda-regional CDATA #FIXED "http://www.ich.org/fda"
xmlns:xlink CDATA #FIXED "http://www.w3c.org/1999/xlink"
xml:lang CDATA #IMPLIED
dtd-version CDATA #FIXED "2.01"
>
<!-- ================== LEAF CONTENT ============================= -->
<!ELEMENT leaf (title, link-text?)>
<!ATTLIST leaf
ID ID #REQUIRED
application-version CDATA #IMPLIED
version CDATA #IMPLIED
font-library CDATA #IMPLIED
operation (new | append | replace | delete) #REQUIRED
modified-file CDATA #IMPLIED
checksum CDATA #IMPLIED
checksum-type CDATA #IMPLIED
keywords CDATA #IMPLIED
xmlns:xlink CDATA #FIXED "http://www.w3c.org/1999/xlink"
xlink:type CDATA #FIXED "simple"
xlink:role CDATA #IMPLIED
xlink:href CDATA #IMPLIED
xlink:show (new | replace | embed | other | none) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none) #IMPLIED

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The eCTD Backbone Files Specification for Module 1


xml:lang CDATA #IMPLIED

>
<!ELEMENT title (#PCDATA)>
<!ATTLIST title
ID ID #IMPLIED
>
<!ELEMENT link-text (#PCDATA | xref)*>
<!ATTLIST link-text
ID ID #IMPLIED
>
<!ELEMENT xref EMPTY>
<!ATTLIST xref
ID ID #IMPLIED
xmlns:xlink CDATA #FIXED "http://www.w3c.org/1999/xlink"
xlink:type CDATA #FIXED "simple"
xlink:role CDATA #IMPLIED
xlink:title CDATA #REQUIRED
xlink:href CDATA #REQUIRED
xlink:show (new | replace | embed | other | none) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none) #IMPLIED
>
<!ELEMENT node-extension (title, (leaf | node-extension)+)>
<!ATTLIST node-extension
ID ID #IMPLIED
xml:lang CDATA #IMPLIED
>
<!-- ================== ADMIN ==================================== -->
<!ELEMENT admin (applicant-info, product-description, application-information)>
<!-- ********************* Applicant Information ******************** -->
<!ELEMENT applicant-info (company-name, date-of-submission)>
<!ELEMENT company-name (#PCDATA)>
<!ELEMENT date-of-submission (date)>
<!ELEMENT date (#PCDATA)>
<!ATTLIST date
format (yyyymmdd) #REQUIRED
>
<!-- ********************* Product Description ********************** -->
<!ELEMENT product-description (application-number, prod-name+)>
<!ELEMENT application-number (#PCDATA)>
<!ELEMENT prod-name (#PCDATA)>
<!ATTLIST prod-name
type (established | proprietary | chemical | code) #REQUIRED
>
<!-- ********************* Application Information ****************** -->
<!ELEMENT application-information (submission)>
<!ATTLIST application-information

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The eCTD Backbone Files Specification for Module 1


application-type (nda | anda | bla | dmf | ind | master-file) #REQUIRED

>
<!ELEMENT submission (sequence-number, related-sequence-number*)>
<!ATTLIST submission
submission-type (
original-application |
amendment |
resubmission |
presubmission |
annual-report |
establishment-description-supplement |
efficacy-supplement | labeling-supplement |
chemistry-manufacturing-controls-supplement |
other) #REQUIRED
>
<!ELEMENT sequence-number (#PCDATA)>
<!ELEMENT related-sequence-number (#PCDATA)>
<!-- ================= M1 REGIONAL STRUCTURE ==================== -->
<!ELEMENT m1-regional (
m1-1-forms?,
m1-2-cover-letters?,
m1-3-administrative-information?,
m1-4-references?,
m1-5-application-status?,
m1-6-meetings?,
m1-7-fast-track?,
m1-8-special-protocol-assessment-request?,
m1-9-pediatric-administrative-information?,
m1-10-dispute-resolution?,
m1-11-information-amendment?,
m1-12-other-correspondence?,
m1-13-annual-report?,
m1-14-labeling?,
m1-15-promotional-material?,
m1-16-risk-management-plans?)>
<!ATTLIST m1-regional
%att;
>
<!-- ================= FORMS ==================================== -->
<!ELEMENT m1-1-forms (
m1-1-1-fda-form-1571?,
m1-1-2-fda-form-356h?,
m1-1-3-fda-form-3397?,
m1-1-4-fda-form-2252?,
m1-1-5-fda-form-2253?,
m1-1-6-fda-form-2567?)>

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The eCTD Backbone Files Specification for Module 1


<!ATTLIST m1-1-forms
%att;
>
<!ELEMENT m1-1-1-fda-form-1571 ((leaf | node-extension)*)>
<!ATTLIST m1-1-1-fda-form-1571
%att;
>
<!ELEMENT m1-1-2-fda-form-356h ((leaf | node-extension)*)>
<!ATTLIST m1-1-2-fda-form-356h
%att;
>
<!ELEMENT m1-1-3-fda-form-3397 ((leaf | node-extension)*)>
<!ATTLIST m1-1-3-fda-form-3397
%att;
>
<!ELEMENT m1-1-4-fda-form-2252 ((leaf | node-extension)*)>
<!ATTLIST m1-1-4-fda-form-2252
%att;
>
<!ELEMENT m1-1-5-fda-form-2253 ((leaf | node-extension)*)>
<!ATTLIST m1-1-5-fda-form-2253
%att;
>
<!ELEMENT m1-1-6-fda-form-2567 ((leaf | node-extension)*)>
<!ATTLIST m1-1-6-fda-form-2567
%att;
>
<!-- ================= COVER LETTERS ============================ -->
<!ELEMENT m1-2-cover-letters ((leaf | node-extension)*)>
<!ATTLIST m1-2-cover-letters
%att;
>
<!-- ================== ADMINISTRATIVE INFORMATION =============== -->
<!ELEMENT m1-3-administrative-information (
m1-3-1-applicant-information*,
m1-3-2-field-copy-certification*,
m1-3-3-debarment-certification*,
m1-3-4-financial-certification-disclosure*,
m1-3-5-patent-exclusivity*)>
<!ATTLIST m1-3-administrative-information
%att;
>
<!ELEMENT m1-3-1-applicant-information (
m1-3-1-1-change-of-address-or-corporate-name*,
m1-3-1-2-change-contact-agent*,
m1-3-1-3-change-in-sponsor*,

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m1-3-1-4-transfer-obligation*,
m1-3-1-5-change-application-ownership*)>
<!ATTLIST m1-3-1-applicant-information
%att;
>
<!ELEMENT m1-3-1-1-change-of-address-or-corporate-name
((leaf | node-extension)*)>
<!ATTLIST m1-3-1-1-change-of-address-or-corporate-name
%att;
>
<!ELEMENT m1-3-1-2-change-contact-agent ((leaf | node-extension)*)>
<!ATTLIST m1-3-1-2-change-contact-agent
%att;
>
<!ELEMENT m1-3-1-3-change-in-sponsor ((leaf | node-extension)*)>
<!ATTLIST m1-3-1-3-change-in-sponsor
%att;
>
<!ELEMENT m1-3-1-4-transfer-obligation ((leaf | node-extension)*)>
<!ATTLIST m1-3-1-4-transfer-obligation
%att;
>
<!ELEMENT m1-3-1-5-change-application-ownership ((leaf | node-extension)*)>
<!ATTLIST m1-3-1-5-change-application-ownership
%att;
>
<!-- =================== FIELD COPY CERTIFICATION ================= -->
<!ELEMENT m1-3-2-field-copy-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-2-field-copy-certification
%att;
>
<!-- ================= DEBARMENT CERTIFICATION ================== -->
<!ELEMENT m1-3-3-debarment-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-3-debarment-certification
%att;
>
<!-- ================== FINANCIAL CERTIFICATION DISCLOSURE ======= -->
<!ELEMENT m1-3-4-financial-certification-disclosure ((leaf | node-extension)*)>
<!ATTLIST m1-3-4-financial-certification-disclosure
%att;
>
<!-- ===================== PATENT EXCLUSIVITIY ====================== ->
<!ELEMENT m1-3-5-patent-exclusivity (
m1-3-5-1-patent-information*,
m1-3-5-2-patent-certification*,

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m1-3-5-3-exclusivity-request*)>
<!ATTLIST m1-3-5-patent-exclusivity
%att;
>
<!ELEMENT m1-3-5-1-patent-information ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-1-patent-information
%att;
>
<!ELEMENT m1-3-5-2-patent-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-2-patent-certification
%att;
>
<!ELEMENT m1-3-5-3-exclusivity-request ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-3-exclusivity-request
%att;
>
<!-- ================= REFERENCES =============================== -->
<!ELEMENT m1-4-references (
m1-4-1-letter-authorization*,
m1-4-2-statement-right-reference*,
m1-4-3-list-of-authorized-persons-to-incorporate-by-reference*,
m1-4-4-cross-reference-other-applications*)>
<!ATTLIST m1-4-references
%att;
>
<!ELEMENT m1-4-1-letter-authorization ((leaf | node-extension)*)>
<!ATTLIST m1-4-1-letter-authorization
%att;
>
<!ELEMENT m1-4-2-statement-right-reference ((leaf | node-extension)*)>
<!ATTLIST m1-4-2-statement-right-reference
%att;
>
<!ELEMENT m1-4-3-list-of-authorized-persons-to-incorporate-by-reference
((leaf | node-extension)*)>
<!ATTLIST m1-4-3-list-of-authorized-persons-to-incorporate-by-reference
%att;
>
<!ELEMENT m1-4-4-cross-reference-other-applications ((leaf | node-extension)*)>
<!ATTLIST m1-4-4-cross-reference-other-applications
%att;
>
<!-- ================== APPLICATION STATUS ======================= -->
<!ELEMENT m1-5-application-status (
m1-5-1-withdrawal-request*,
m1-5-2-inactivation-request*,

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The eCTD Backbone Files Specification for Module 1


m1-5-3-reactivation-request*,
m1-5-4-reinstatement-request*,
m1-5-5-withdrawal-unapproved-nda*,
m1-5-6-withdrawal-of-listed-drug*,
m1-5-7-request-withdrawal-application-approval*)>
<!ATTLIST m1-5-application-status
%att;
>
<!ELEMENT m1-5-1-withdrawal-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-1-withdrawal-request
%att;
>
<!ELEMENT m1-5-2-inactivation-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-2-inactivation-request
%att;
>
<!ELEMENT m1-5-3-reactivation-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-3-reactivation-request
%att;
>
<!ELEMENT m1-5-4-reinstatement-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-4-reinstatement-request
%att;
>
<!ELEMENT m1-5-5-withdrawal-unapproved-nda ((leaf | node-extension)*)>
<!ATTLIST m1-5-5-withdrawal-unapproved-nda
%att;
>
<!ELEMENT m1-5-6-withdrawal-of-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-5-6-withdrawal-of-listed-drug
%att;
>
<!ELEMENT m1-5-7-request-withdrawal-application-approval ((leaf | node-extension)*)>
<!ATTLIST m1-5-7-request-withdrawal-application-approval
%att;
>
<!-- ================== MEETINGS ================================= -->
<!ELEMENT m1-6-meetings (m1-6-1-meeting-request*, m1-6-2-meeting-backgroundmaterials*, m1-6-3-correspondence-regarding-meetings*)>
<!ATTLIST m1-6-meetings
%att;
>
<!ELEMENT m1-6-1-meeting-request ((leaf | node-extension)*)>
<!ATTLIST m1-6-1-meeting-request
%att;
>

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The eCTD Backbone Files Specification for Module 1


<!ELEMENT m1-6-2-meeting-background-materials ((leaf | node-extension)*)>
<!ATTLIST m1-6-2-meeting-background-materials
%att;
>
<!ELEMENT m1-6-3-correspondence-regarding-meetings ((leaf | node-extension)*)>
<!ATTLIST m1-6-3-correspondence-regarding-meetings
%att;
>
<!-- ================== FAST TRACK =============================== -->
<!ELEMENT m1-7-fast-track (
m1-7-1-fast-track-designation-request*,
m1-7-2-fast-track-designation-withdrawal-request*,
m1-7-3-rolling-review-request*)>
<!ATTLIST m1-7-fast-track
%att;
>
<!ELEMENT m1-7-1-fast-track-designation-request ((leaf | node-extension)*)>
<!ATTLIST m1-7-1-fast-track-designation-request
%att;
>
<!ELEMENT m1-7-2-fast-track-designation-withdrawal-request
((leaf | node-extension)*)>
<!ATTLIST m1-7-2-fast-track-designation-withdrawal-request
%att;
>
<!ELEMENT m1-7-3-rolling-review-request ((leaf | node-extension)*)>
<!ATTLIST m1-7-3-rolling-review-request
%att;
>
<!-- =============== SPECIAL PROTOCOL ASSESSMENT REQUEST ====== -->
<!ELEMENT m1-8-special-protocol-assessment-request (
m1-8-1-clinical-study*,
m1-8-2-carcinogenicity-study*,
m1-8-3-stability-study*)>
<!ATTLIST m1-8-special-protocol-assessment-request
%att;
>
<!ELEMENT m1-8-1-clinical-study ((leaf | node-extension)*)>
<!ATTLIST m1-8-1-clinical-study
%att;
>
<!ELEMENT m1-8-2-carcinogenicity-study ((leaf | node-extension)*)>
<!ATTLIST m1-8-2-carcinogenicity-study
%att;
>
<!ELEMENT m1-8-3-stability-study ((leaf | node-extension)*)>

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<!ATTLIST m1-8-3-stability-study
%att;
>
<!-- ================== PEDIATRIC ADMINISTRATIVE INFORMATION ===== -->
<!ELEMENT m1-9-pediatric-administrative-information (
m1-9-1-request-waiver-pediatric-studies*,
m1-9-2-request-deferral-pediatric-studies*,
m1-9-3-request-pediatric-exclusivity-determination*,
m1-9-4-proposed-pediatric-study-request-amendments*,
m1-9-5-proposal-written-agreement*,
m1-9-6-other-correspondence-regarding-pediatric-exclusivity-study-plans*)>
<!ATTLIST m1-9-pediatric-administrative-information
%att;
>
<!ELEMENT m1-9-1-request-waiver-pediatric-studies ((leaf | node-extension)*)>
<!ATTLIST m1-9-1-request-waiver-pediatric-studies
%att;
>
<!ELEMENT m1-9-2-request-deferral-pediatric-studies ((leaf | node-extension)*)>
<!ATTLIST m1-9-2-request-deferral-pediatric-studies
%att;
>
<!ELEMENT m1-9-3-request-pediatric-exclusivity-determination
((leaf | node-extension)*)>
<!ATTLIST m1-9-3-request-pediatric-exclusivity-determination
%att;
>
<!ELEMENT m1-9-4-proposed-pediatric-study-request-amendments
((leaf | node-extension)*)>
<!ATTLIST m1-9-4-proposed-pediatric-study-request-amendments
%att;
>
<!ELEMENT m1-9-5-proposal-written-agreement ((leaf | node-extension)*)>
<!ATTLIST m1-9-5-proposal-written-agreement
%att;
>
<!ELEMENT m1-9-6-other-correspondence-regarding-pediatric-exclusivity-study-plans
((leaf | node-extension)*)>
<!ATTLIST m1-9-6-other-correspondence-regarding-pediatric-exclusivity-study-plans
%att;
>
<!-- ================== DISPUTE RESOLUTION ======================= -->
<!ELEMENT m1-10-dispute-resolution (
m1-10-1-request-for-dispute-resolution*,
m1-10-2-correspondence-related-to-dispute-resolution*)>
<!ATTLIST m1-10-dispute-resolution

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%att;

>
<!ELEMENT m1-10-1-request-for-dispute-resolution ((leaf | node-extension)*)>
<!ATTLIST m1-10-1-request-for-dispute-resolution
%att;
>
<!ELEMENT m1-10-2-correspondence-related-to-dispute-resolution ((leaf | node-extension)*)>
<!ATTLIST m1-10-2-correspondence-related-to-dispute-resolution
%att;
>
<!-- ================ INFORMATION ADMENDMENT =================== -->
<!ELEMENT m1-11-information-amendment (
m1-11-1-quality-information-amendment*,
m1-11-2-safety-information-amendment*,
m1-11-3-efficacy-information-amendment*,
m1-11-4-multiple-module-information-amendments*)>
<!ATTLIST m1-11-information-amendment
%att;
>
<!ELEMENT m1-11-1-quality-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-1-quality-information-amendment
%att;
>
<!ELEMENT m1-11-2-safety-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-2-safety-information-amendment
%att;
>
<!ELEMENT m1-11-3-efficacy-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-3-efficacy-information-amendment
%att;
>
<!ELEMENT m1-11-4-multiple-module-information-amendments
((leaf | node-extension)*)>
<!ATTLIST m1-11-4-multiple-module-information-amendments
%att;
>
<!-- =============== OTHER CORRESPONDENCE ===================== -->
<!ELEMENT m1-12-other-correspondence (
m1-12-1-pre-ind-correspondence*,
m1-12-2-request-charge*,
m1-12-3-notification-charging-under-treatment-ind*,
m1-12-4-request-comments-advice-ind*,
m1-12-5-request-waiver*,
m1-12-6-exemption-informed-consent-emergency-research*,
m1-12-7-public-disclosure-statement-emergency-care-research*,
m1-12-8-correspondence-regarding-emergency-care-research*,

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m1-12-9-notification-discontinuation-clinical-trial*,
m1-12-10-generic-drug-enforcement-act-statement*,
m1-12-11-basis-submission-statement*,
m1-12-12-comparison-generic-drug-reference-listed-drug*,
m1-12-13-request-waiver-in-vivo-studies*,
m1-12-14-environmental-analysis*,
m1-12-15-request-waiver-in-vivo-bioavailability-studies*,
m1-12-16-field-alert-reports*)>
<!ATTLIST m1-12-other-correspondence
%att;
>
<!ELEMENT m1-12-1-pre-ind-correspondence ((leaf | node-extension)*)>
<!ATTLIST m1-12-1-pre-ind-correspondence
%att;
>
<!ELEMENT m1-12-2-request-charge ((leaf | node-extension)*)>
<!ATTLIST m1-12-2-request-charge
%att;
>
<!ELEMENT m1-12-3-notification-charging-under-treatment-ind
((leaf | node-extension)*)>
<!ATTLIST m1-12-3-notification-charging-under-treatment-ind
%att;
>
<!ELEMENT m1-12-4-request-comments-advice-ind ((leaf | node-extension)*)>
<!ATTLIST m1-12-4-request-comments-advice-ind
%att;
>
<!ELEMENT m1-12-5-request-waiver ((leaf | node-extension)*)>
<!ATTLIST m1-12-5-request-waiver
%att;
>
<!ELEMENT m1-12-6-exemption-informed-consent-emergency-research
((leaf | node-extension)*)>
<!ATTLIST m1-12-6-exemption-informed-consent-emergency-research
%att;
>
<!ELEMENT m1-12-7-public-disclosure-statement-emergency-care-research
((leaf | node-extension)*)>
<!ATTLIST m1-12-7-public-disclosure-statement-emergency-care-research
%att;
>
<!ELEMENT m1-12-8-correspondence-regarding-emergency-care-research
((leaf | node-extension)*)>
<!ATTLIST m1-12-8-correspondence-regarding-emergency-care-research
%att;

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The eCTD Backbone Files Specification for Module 1


>
<!ELEMENT m1-12-9-notification-discontinuation-clinical-trial ((leaf | node-extension)*)>
<!ATTLIST m1-12-9-notification-discontinuation-clinical-trial
%att;
>
<!ELEMENT m1-12-10-generic-drug-enforcement-act-statement
((leaf | node-extension)*)>
<!ATTLIST m1-12-10-generic-drug-enforcement-act-statement
%att;
>
<!ELEMENT m1-12-11-basis-submission-statement ((leaf | node-extension)*)>
<!ATTLIST m1-12-11-basis-submission-statement
%att;
>
<!ELEMENT m1-12-12-comparison-generic-drug-reference-listed-drug
((leaf | node-extension)*)>
<!ATTLIST m1-12-12-comparison-generic-drug-reference-listed-drug
%att;
>
<!ELEMENT m1-12-13-request-waiver-in-vivo-studies ((leaf | node-extension)*)>
<!ATTLIST m1-12-13-request-waiver-in-vivo-studies
%att;
>
<!ELEMENT m1-12-14-environmental-analysis ((leaf | node-extension)*)>
<!ATTLIST m1-12-14-environmental-analysis
%att;
>
<!ELEMENT m1-12-15-request-waiver-in-vivo-bioavailability-studies
((leaf | node-extension)*)>
<!ATTLIST m1-12-15-request-waiver-in-vivo-bioavailability-studies
%att;
>
<!ELEMENT m1-12-16-field-alert-reports ((leaf | node-extension)*)>
<!ATTLIST m1-12-16-field-alert-reports
%att;
>
<!-- ================= ANNUAL REPORT ============================ -->
<!ELEMENT m1-13-annual-report (
m1-13-1-summary-nonclinical-studies*,
m1-13-2-summary-clinical-pharmacology-information*,
m1-13-3-summary-safety-information*,
m1-13-4-summary-labeling-changes*,
m1-13-5-summary-manufacturing-changes*,
m1-13-6-summary-microbiological-changes*,
m1-13-7-summary-other-significant-new-information*,
m1-13-8-individual-study-information*,

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m1-13-9-general-investigational-plan*,
m1-13-10-foreign-marketing-history*,
m1-13-11-distribution-data*,
m1-13-12-status-postmarketing-study-commitments*,
m1-13-13-status-other-postmarketing-studies*,
m1-13-14-log-outstanding-regulatory-business*)>
<!ATTLIST m1-13-annual-report
%att;
>
<!ELEMENT m1-13-1-summary-nonclinical-studies ((leaf | node-extension)*)>
<!ATTLIST m1-13-1-summary-nonclinical-studies
%att;
>
<!ELEMENT m1-13-2-summary-clinical-pharmacology-information
((leaf | node-extension)*)>
<!ATTLIST m1-13-2-summary-clinical-pharmacology-information
%att;
>
<!ELEMENT m1-13-3-summary-safety-information ((leaf | node-extension)*)>
<!ATTLIST m1-13-3-summary-safety-information
%att;
>
<!ELEMENT m1-13-4-summary-labeling-changes ((leaf | node-extension)*)>
<!ATTLIST m1-13-4-summary-labeling-changes
%att;
>
<!ELEMENT m1-13-5-summary-manufacturing-changes ((leaf | node-extension)*)>
<!ATTLIST m1-13-5-summary-manufacturing-changes
%att;
>
<!ELEMENT m1-13-6-summary-microbiological-changes ((leaf | node-extension)*)>
<!ATTLIST m1-13-6-summary-microbiological-changes
%att;
>
<!ELEMENT m1-13-7-summary-other-significant-new-information
((leaf | node-extension)*)>
<!ATTLIST m1-13-7-summary-other-significant-new-information
%att;
>
<!ELEMENT m1-13-8-individual-study-information ((leaf | node-extension)*)>
<!ATTLIST m1-13-8-individual-study-information
%att;
>
<!ELEMENT m1-13-9-general-investigational-plan ((leaf | node-extension)*)>
<!ATTLIST m1-13-9-general-investigational-plan
%att;

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>
<!ELEMENT m1-13-10-foreign-marketing-history ((leaf | node-extension)*)>
<!ATTLIST m1-13-10-foreign-marketing-history
%att;
>
<!ELEMENT m1-13-11-distribution-data ((leaf | node-extension)*)>
<!ATTLIST m1-13-11-distribution-data
%att;
>
<!ELEMENT m1-13-12-status-postmarketing-study-commitments
((leaf | node-extension)*)>
<!ATTLIST m1-13-12-status-postmarketing-study-commitments
%att;
>
<!ELEMENT m1-13-13-status-other-postmarketing-studies ((leaf | node-extension)*)>
<!ATTLIST m1-13-13-status-other-postmarketing-studies
%att;
>
<!ELEMENT m1-13-14-log-outstanding-regulatory-business ((leaf | node-extension)*)>
<!ATTLIST m1-13-14-log-outstanding-regulatory-business
%att;
>
<!-- ===================== LABELING ================================= ->
<!ELEMENT m1-14-labeling (
m1-14-1-draft-labeling*,
m1-14-2-final-labeling*,
m1-14-3-listed-drug-labeling*,
m1-14-4-investigational-drug-labeling*,
m1-14-5-foreign-labeling*)>
<!ATTLIST m1-14-labeling
%att;
>
<!ELEMENT m1-14-1-draft-labeling (
m1-14-1-1-draft-carton-container-labels*,
m1-14-1-2-annotated-draft-labeling-text*,
m1-14-1-3-draft-labeling-text*,
m1-14-1-4-label-comprehension-studies*,
m1-14-1-5-labeling-history*)>
<!ATTLIST m1-14-1-draft-labeling
%att;
>
<!ELEMENT m1-14-1-1-draft-carton-container-labels ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-1-draft-carton-container-labels
%att;
>

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The eCTD Backbone Files Specification for Module 1


<!ELEMENT m1-14-1-2-annotated-draft-labeling-text ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-2-annotated-draft-labeling-text
%att;
>
<!ELEMENT m1-14-1-3-draft-labeling-text ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-3-draft-labeling-text
%att;
>
<!ELEMENT m1-14-1-4-label-comprehension-studies ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-4-label-comprehension-studies
%att;
>
<!ELEMENT m1-14-1-5-labeling-history ((leaf | node-extension)*)>
<!ATTLIST m1-14-1-5-labeling-history
%att;
>
<!ELEMENT m1-14-2-final-labeling (
m1-14-2-1-final-carton-container-labels*,
m1-14-2-2-final-package-insert-package-inserts*,
m1-14-2-3-final-labeling-text*)>
<!ATTLIST m1-14-2-final-labeling
%att;
>
<!ELEMENT m1-14-2-1-final-carton-container-labels ((leaf | node-extension)*)>
<!ATTLIST m1-14-2-1-final-carton-container-labels
%att;
>
<!ELEMENT m1-14-2-2-final-package-insert-package-inserts ((leaf | node-extension)*)>
<!ATTLIST m1-14-2-2-final-package-insert-package-inserts
%att;
>
<!ELEMENT m1-14-2-3-final-labeling-text ((leaf | node-extension)*)>
<!ATTLIST m1-14-2-3-final-labeling-text
%att;
>
<!ELEMENT m1-14-3-listed-drug-labeling (
m1-14-3-1-annotated-comparison-listed-drug*,
m1-14-3-2-approved-labeling-text-listed-drug*,
m1-14-3-3-labeling-text-reference-listed-drug*)>
<!ATTLIST m1-14-3-listed-drug-labeling
%att;
>
<!ELEMENT m1-14-3-1-annotated-comparison-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-14-3-1-annotated-comparison-listed-drug
%att;
>

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<!ELEMENT m1-14-3-2-approved-labeling-text-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-14-3-2-approved-labeling-text-listed-drug
%att;
>
<!ELEMENT m1-14-3-3-labeling-text-reference-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-14-3-3-labeling-text-reference-listed-drug
%att;
>
<!ELEMENT m1-14-4-investigational-drug-labeling (
m1-14-4-1-investigational-brochure*,
m1-14-4-2-investigational-drug-label*)>
<!ATTLIST m1-14-4-investigational-drug-labeling
%att;
>
<!ELEMENT m1-14-4-1-investigational-brochure ((leaf | node-extension)*)>
<!ATTLIST m1-14-4-1-investigational-brochure
%att;
>
<!ELEMENT m1-14-4-2-investigational-drug-label ((leaf | node-extension)*)>
<!ATTLIST m1-14-4-2-investigational-drug-label
%att;
>
<!ELEMENT m1-14-5-foreign-labeling ((leaf | node-extension)*)>
<!ATTLIST m1-14-5-foreign-labeling
%att;
>
<!-- ================= PROMOTIONAL MATERIAL ===================== -->
<!ELEMENT m1-15-promotional-material ((leaf | node-extension)*)>
<!ATTLIST m1-15-promotional-material
%att;
>
<!-- ================== RISK MANAGEMENT ========================= -->
<!ELEMENT m1-16-risk-management-plans ((leaf | node-extension)*)>
<!ATTLIST m1-16-risk-management-plans
%att;
>

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SECTION 9

eCTD Backbone Files Specifications


for Module 2 through 5

This document provides specifications for creating the eCTD backbone file for
Modules 2 to 5 of the common technical document (CTD) for use with the
guidance to industry: Providing Regulatory Submissions in Electronic Format
Human Pharmaceutical Applications and Related Submissions.

The eCTD Backbone File Specification for Modules 2 through 5

The eCTD Backbone File Specification for Modules 2 through 5


Revision History
Date
Version
2003-08-13
1.0
2004-03-11
1.1

Summary of Changes
Original version
Clarifications to the original version

The eCTD Backbone File Specification for Modules 2 through 5

I.

START AND FINISH OF THE MODULE 2 TO 5 ECTD BACKBONE FILE.........................................3

II.

LEAF ELEMENT ..............................................................................................................................................4


A.
B.
C.
D.
E.
F.
G.
H.
I.
J.

START TAG FOR THE LEAF ELEMENT................................................................................................................5


ID ATTRIBUTE FOR LEAF ELEMENT ..................................................................................................................5
OPERATION ATTRIBUTE FOR THE LEAF ELEMENT .............................................................................................6
MODIFIED-FILE ATTRIBUTE FOR THE LEAF ELEMENT ........................................................................................6
CHECKSUM ATTRIBUTE FOR THE LEAF ELEMENT ..............................................................................................7
CHECKSUM-TYPE ATTRIBUTE FOR THE LEAF ELEMENT .....................................................................................7
XLINK:HREF ATTRIBUTE FOR THE LEAF ELEMENT .............................................................................................8
XLINK:SHOW ATTRIBUTE ..................................................................................................................................8
TITLE CHILD ELEMENT OF THE LEAF ELEMENT .................................................................................................8
END TAG FOR THE LEAF ELEMENT ...................................................................................................................9

III. HEADING ELEMENT......................................................................................................................................9


A.
B.
C.
D.

HEADING ELEMENTS ATTRIBUTES FOR MODULE 2 .........................................................................................11


HEADING ELEMENTS AND ATTRIBUTES FOR MODULE 3..................................................................................14
HEADING ELEMENTS AND ATTRIBUTES FOR MODULE 4 ..................................................................................23
HEADING ELEMENTS AND ATTRIBUTES FOR MODULE 5 ..................................................................................28

The eCTD Backbone File Specification for Modules 2 through 5

The eCTD Backbone Files Specification for Modules 2 through 5


(Module 2 to 5 eCTD Backbone File)
This document provides specifications for creating the electronic common technical document
(eCTD) backbone file for modules 2 to 5 of the common technical document (CTD) for use with
the guidance to industry: Providing Regulatory Submissions in Electronic Format Human
Pharmaceutical Applications and Related Submissions.
The Module 2 to 5 eCTD Backbone File includes information for each file submitted in modules
2 to 5. The file information is provided within an XML element called the leaf element. The leaf
elements are organized using the CTD headings. The CTD headings are named and organized
according to the subject matter of the information contained in the file. The heading information
is provided in an XML element called heading elements.
Because the Module 2 to 5 eCTD Backbone File may be used in a wide range of applications and
related submission types, a specific submission will not use all of the possible heading elements.
You should only include the heading elements needed to organize the files in your submission.
I. START AND FINISH OF THE MODULE 2 TO 5 ECTD BACKBONE FILE
You should name the Module 2 to 5 eCTD Backbone File index.xml and place it in the main
submission folder as described in Providing Regulatory Submissions in Electronic Format
Human Pharmaceutical Applications and Related Submissions. For example, the path for the
index.xml for sequence number 0006 is ../0006/index.xml.
The header contains the root element, <ectd:ectd> and the last element, </ectd:ectd>1 of the
Module 2 to 5 eCTD Backbone File. This is always the same. The header contains information
about the following:
1.
2.
3.
4.
5.

Version of XML being used


Type of characters that are allowed in the file
Location of the standards that control the organization of the eCTD backbone files
Organization element and Leaf element for the Module 1 eCTD Backbone File
Indication that the file information is ended (end tag)

A sample of the header and the last line of the Module 2 to 5 eCTD Backbone File is provided
below:
<?xml version = "1.0" encoding = "UTF-8"?>
<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-0.dtd">
<ectd:ectd
xmlns:ectd = "http://www.ich.org/ectd"
xmlns:xlink = "http://www.w3c.org/1999/xlink">
1

This is the end tag for the root element.

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<!--All the heading elements and content for module 2, 3, 4, and module 5
will be provided after these elements and before the last element closing
tag named </ectd:ectd> -->
</ectd:ectd>
The elements used to organize files for Modules 2 to 5 are placed within the area represented by
the comment in the example shown above. Information about creating those elements is
provided in other sections of this specification.
II. LEAF ELEMENT
Information for an individual file is contained in the leaf element, its attributes and its title
element. The leaf element is used repeatedly throughout the eCTD backbone file to provide
individual information for each submitted file.
The table below provides the name of each part of the leaf element and a brief indication of its
purpose:
Part of "leaf" Element
<leaf>
ID
operation
modified-file
checksum
checksum-type
xlink:href
xlink:show
title

</leaf>

Purpose of leaf Element Part


Tag indicating start of leaf element to organize the information for .
each submitted file.
This attribute provides a unique identification of the leaf element in
the submission.
This attribute provides information about the life cycle of the leaf.
This attribute provides the ID of a previously submitted leaf that is
effected by the operation attribute in the current submission, if
applicable .
This attribute provides the document's checksum value (Also
known as document's "hash").
This attribute provides the type of checksum that is in the checksum
attribute. ICH currently uses a 128 bit checksum or message
digest generated by the MD5 algorithm.
This attribute provides the location of the file using the files path.
This attribute has not yet been defined within ICH
This element provides the title of the document to help the reader
identify the subject matter. Do not include information in the title
already in other areas of the backbone files in the title e.g.,
application number, heading names).
Tag indicating end of leaf element.

The following is an example of the leaf element for a file containing the first version of the
tabular listing of all clinical studies provided in module 5.
<leaf >
ID="a1234567"
operation="new"

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The eCTD Backbone File Specification for Modules 2 through 5


modified-file=""
checksum="9f52fcd71d726c74faf07c85d46b3363"
checksum-type="md5"
xlink:href="m5/tabular-listing-of-studies.pdf"
<title>Tabular listing of all clinical studies</title>
</leaf>
For the remainder of this section each part of the leaf element is described in detail in its own
subsection.
A. Start Tag for the leaf Element
The purpose of the start tag is to provide a machine-readable indication that file information is
beginning. All the leaf element attributes and the title element are contained between the leaf
start tag and the leaf end tags.
The start tag for the leaf element begins with the "less than" symbol, <, and the lower case
word "leaf". This is followed by each of the leaf element attributes and their values. The leaf
element, its attributes and their values are placed between the word leaf and the closing
greater than symbol of the leaf element start tag.
The leaf element start tag and its matching end tag with all the attribute and element contents are
used for each file being submitted, modified or referenced2 to the Agency for review. The leaf
element is the fundamental block of information for every file and occurs in both the Module 2
to 5 eCTD Backbone File and Module 1 eCTD Backbone File.
B. ID Attribute for leaf Element
The purpose of the leaf element ID attribute is to provide a unique identification for the file
within the submission. This facilitates referencing from other submissions. The leaf element ID
combined with the application number, sequence number and name of the eCTD backbone file
provide a unique ID for the file.
The ID attribute occurs after the word leaf and begins with the upper case letters "ID". The
value for the ID attribute is provided in a statement that begins with the equal sign and quotation
mark, (="), followed by the ID attribute value ending with a quotation mark. There should be no
spaces in the ID attribute value statement.
The ID value must start with a letter followed by a combination of letters and numbers to provide
a unique identification of this leaf element within the Module 2 to 5 eCTD Backbone File.
Examples of valid ID attributes:

Including previously submitted information. See Guidance to Industry: Providing Regulatory


Submissions in Electronic Format Human Drug Applications and Related Submissions for
more information.
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The eCTD Backbone File Specification for Modules 2 through 5


ID="a1234567"
ID=id12235
ID=pid1234
The following are invalid values for the ID attribute:
ID=123a456
ID=1234567
ID=a 1246

- does not start with a letter


- does not have a letter
- includes a space

You should provide an ID attribute and value for each leaf element that is unique for the
submission.
C. Operation attribute for the leaf element
The purpose of the operation attribute is to provide a machine-readable indication of the effect
this leaf has on a leaf included in previously submitted eCTD backbone files.
You should include an operation attribute for each leaf you are submitting. The value for the
operation attribute is limited to: new, append, replace, and delete. The table below summarizes
the meaning of each modified-file attribute value.
Attribute and Value
operation ="new"
operation ="append"

operation ="replace"
operation ="delete"

Meaning
This means that the leaf does not have an effect on a leaf included in
previously submitted eCTD backbone files.
This means that the file contained in the current leaf provides
information that is in addition to information in a file contained in a
leaf previously submitted eCTD backbone file. If there are a series of
files appending an original file, only append the original file. You
should not append a file that append another file.
This means the file contained in the current leaf replaces a file
contained in a leaf in a previously submitted eCTD backbone file.
This means a file contained in a leaf in a previously submitted eCTD
backbone file should no longer be considered in the evaluation of the
application. In this situation, there is no file provided for the leaf.

D. Modified-file attribute for the leaf element


The purpose of the modified-file attribute is to provide the location of leaf that is being modified
(i.e. appended, replaced, or deleted) by the current leaf element. The modified-file attribute
should have a value when the operation attribute has a value of append, replace or delete.
The modified-file attribute for the leaf element begins with the lowercase hyphenated word
"modified-file". The value for the modified-file attribute is provided in a statement that begins
with the equal sign and quotation mark, (="), followed by the modified-file attribute value and

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ending with a quotation mark. There should be no spaces in the modified-file attribute's value
statement.
The modified-file leaf attribute should have a value of a relative path and filename with a
bookmark. You should use the relative path and filename for the eCTD backbone file (ie.,
index.xml or us-regional.xml) containing the modified files leaf element. You should append
the modified files leaf ID value to the relative path and file name as a bookmark. This is
detailed in the next paragraph.
The relative path and filename for a previously submitted leaf will start with two periods and a
slash, ../, providing a machine readable instruction to move up one level in the directory
structure to where the previous submission folders are located. These characters are followed
with the sequence folder name (four numbers, e.g. 0001) and another slash. This is followed by
the path and filename for the leaf you want to modify. For example, to replace the tabular-listingstudies.pdf file submitted in Module 5 of the original submission associated with the leaf ID
value id12345, the modified-file attribute value is as follows:
modified-file="../0000/index.xml#id12345 "
E. checksum attribute for the leaf element
The purpose of the checksum attribute is to provide the value of the checksum for the file this
leaf is providing. The checksum is the result of an algorithm that breaks down a file into a
unique128 bit message digest or fingerprint. The fingerprint is used to verify that the file
was transmitted and received without being modified3.
The checksum attribute for the leaf element begins with the lowercase word "checksum". The
value for the checksum attribute is provided in a statement that begins with the equal sign and
quotation mark, (="), followed by the checksum attribute value and ending with a quotation
mark. There should be no spaces in the checksum attribute's value statement. An example of a
checksum attribute and its value is provided:
checksum="e854d3002c02a61fe5cbe92fd97b0018"
You should provide a checksum attribute and value for every leaf element that includes a file.
F. checksum-type attribute for the leaf element
The checksum-type attribute provides the name of the algorithm used to produce the checksum
value. It should unambiguously identify the algorithm being used.
The checksum-type attribute for the leaf element begins with the lowercase hyphenated word
"checksum-type". The value for the checksum-type attribute is provided in a statement that
begins with the equal sign and quotation mark, (="), followed by the checksum-type attribute
3

Checksum value is also known as the document hash.

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The eCTD Backbone File Specification for Modules 2 through 5


value and ending with a quotation mark. There should be no spaces in the checksum-type
attribute's value statement. An example of a checksum-type attribute and its value is provided:
checksum-type="MD5"
You should provide a checksum-type attribute and value for every leaf element that contains a
checksum value.
G. xlink:href attribute for the leaf element
The purpose of the xlink:href attribute is to provide the machine-readable location and filename
of the file associated with the leaf element. The location is provided as the relative path and
filename of the document. The relative path should be provided relative to the eCTD backbone
file (i.e., index.xml or us-regional.xml) for the leaf.
The xlink:href attribute for the leaf element begins with the lowercase hyphenated word
"xlink:href". The value for the xlink:href attribute is provided in a statement that begins with the
equal sign and quotation mark, (="), followed by the xlink:href attribute value and ending with a
quotation mark. There should be no spaces in the xlink:href attribute's value statement. The
following is an example of a xlink:href attribute and its value for the tabular-listing-studies.pdf in
module 5 in the same submission:
xlink:href="m5/tabular-listing-studies.pdf "
When linking to a file in a previous submission to the application use ../ to signify the level of
the other submissions of an application. The following is an example of a xlink:href attribute and
its value for the tabular-listing-studies.pdf in module 5 submitted in an earlier submission
(sequence number 0001) in the same application:
xlink:href="../0001/m5/tabular-listing-studies.pdf "
Currently, you cannot link to a file submitted to a different application. However, this capability
will be available in the future.
You should provide an xlink:href attribute and its value for every leaf element that provides a
file.
H. xlink:show attribute
The ICH specification has not yet defined a use for the xlink:show attribute and does not need to
be included. If you do include this attribute, you should have the value of "none" or "new" (for
example., xlink:show="none") for the xlink:show attribute.
I. Title child element of the leaf element

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The purpose of the title element is to provide a title for the file that is meaningful to the human
reader. The title should not include information already provided in the leaf attributes or heading
elements (e.g., module number, table of contents numbers). You can use spaces, upper and lower
case letters and numbers freely.
The title element begins with the "less than" symbol, (<), and the lower case word "title",
followed by the "greater than" symbol, (>). The title content is provided after the greater than
sign. The title element is ended similar to how it is started except a slash is placed between the
less than symbol and the word title. An example of a title element and its content is provided:
<title>Tabular listing of all clinical studies </title>
You should provide a title element and content for every leaf element that provides a file.
J. End Tag for the leaf Element
The end tag for the leaf element is the same as the start tag except that it contains a "/" symbol
after the "less than" symbol, (</), used to start the tag. It occurs after the title element's end tag
and indicates the end of the file information for the leaf element.
III. HEADING ELEMENT
The leaf elements in the eCTD backbone file are organized according to the modules and
headings and subheadings of the CTD. There is a heading element in the Module 2 to 5 eCTD
Backbone File for the CTD headings and many of the subheadings. Each element has a start tag
and an end tag. The element tags start with a "less than" symbol, <, and end with a "greater
than" symbol, >. The name of the element is inserted between these symbols. The heading
elements are completed with an end tag. The end tag is the same as the start tag except it has a
"slash", / after the "less than" symbol, (</). The content for the element (i.e., other heading
elements and leaf elements) occurs between the start tag and the end tag. Leaf elements may be
provided directly within only certain heading elements. In the following example is an isolated
part of the Module 2 to 3 eCTD Backbone File. The heading element m2-common-technicaldocument-summaries contains the heading element m2-2-introduction. The heading element m22-introduction contains the leaf element for the CTD-introduction.pdf file.
<m2-common-technical-document-summaries>
<m2-2-introduction>
<leaf >
ID="a1234567"
operation="new"
checksum=" e854d3002c02a61fe5cbe92fd97b0018"
checksum-type="md5"
xlink:href="m2/CTD-introduction.pdf"
version="Version-1">
<title>Introduction to CTD Submission</title>
</leaf>

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</m2-2-introduction>
</m2-common-technical-document-summaries>
Some of the heading elements in the eCTD backbone file have attributes associated with them to
help in organizing the file information. Each of heading element attributes begins after the
heading element name with a space followed by the lowercase attribute name. The value for the
attribute is provided in a statement that begins with the equal sign and quotation mark, (="),
followed by the attribute's value and ending with a quotation mark. There should be no spaces in
the attribute's value statement.
Some of the attributes occur for more than one element. You should make sure that the attribute
values each of these elements are coordinated so that they are the same when appropriate. The
table, below, lists each heading element attribute name and the element or elements where it can
occur followed by the same information organized with the heading elements listed and their
associated attributes.
Attribute Name
substance

Applicable Heading Element(s)


<m3-2-s-drug-substance>
<m3-2-a-1-facilities-and-equipment>
<m3-2-a-2-adventitious-agents-safety-evaluation>
manufacturer
<m3-2-s-drug-substance>
<m3-2-p-drug-product>
<m3-2-a-1-facilities-and-equipment>
<m3-2-a-2-adventitious-agents-safety-evaluation>
product-name
<m3-2-p-drug-product>
<m3-2-a-1-facilities-and-equipment>
<m3-2-a-2-adventitious-agents-safety-evaluation>
dosageform
<m3-2-p-drug-product>
<m3-2-a-1-facilities-and-equipment>
<m3-2-a-2-adventitious-agents-safety-evaluation>
excipient
<m3-2-p-4-control-of-excipients>
indication
<m2-7-3-summary-of-clinical-efficacy>
<m5-3-5-reports-of-efficacy-and-safety-studies>
Heading Element
Applicable Attribute(s)
<m2-7-3-summary-of-clinical-efficacy>
indication
<m3-2-s-drug-substance>
substance
manufacturer
<m3-2-p-drug-product>
product-name
dosageform
manufacturer
<m3-2-p-4-control-of-excipients>
excipient
<m3-2-a-1-facilities-and-equipment>
manufacturer
substance
dosageform
product-name
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<m3-2-a-2-adventitious-agents-safety-evaluation>

<m5-3-5-reports-of-efficacy-and-safety-studies>

manufacturer
substance
dosageform
product-name
indication

Each of the heading element attributes for the eCTD backbone file is described in detail in the
section of this appendix associated with the CTD module where the element and its attribute
occur.
The heading elements and heading element attributes for modules 2 through 5 are described
below.
A. Heading elements attributes for Module 2
This section describes the heading elements and attribute values relevant to module 2.
1. Heading elements
The module 2 heading elements are summarized in the following table. In some cases, the CTD
may describe more subheadings than appear on this table. Those subheadings should be used as
bookmarks within the individual document. Both the start tag and end tag for each heading
element are provided. If there are one or more subheadings for the heading, the corresponding
element end tag will occur on the table row below the last relevant subheading. The leaf element
is included to show where the leaf elements should be placed. The details for the leaf elements
are not shown on this table to keep it clearer. The leaf elements should only occur where
indicated in this table. A heading element may contain any number of leaf elements. If no
documents are submitted for a heading, you should omit the element for that heading in the
eCTD backbone file.
Module 2 CTD Heading
Module 2: Common Technical
Document (CTD) Summaries
2.2 CTD Introduction

Module 2: Quality Overall Summary


(QOS)
Module 2: Nonclinical Overview

Module 2: Nonclinical Written and

Version 1.1

heading element (leaf element abbreviated for clarity)


<m2-common-technical-document-summaries>
<m2-2-introduction>
<leaf>
</leaf>
</m2-2-introduction>
<m2-3-quality-overall-summary>
<leaf>
</leaf>
</m2-3-quality-overall-summary>
<m2-4-nonclinical-overview>
<leaf>
</leaf>
</m2-4-nonclinical-overview>
<m2-6-nonclinical-written-and-tabulated-summaries>

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The eCTD Backbone File Specification for Modules 2 through 5


Module 2 CTD Heading
Tabulated Summaries (NWTS)
2.6.1 Introduction

heading element (leaf element abbreviated for clarity)

<m2-6-1-introduction>
<leaf>
</leaf>
</m2-6-1-introduction>
2.6.2 Pharmacology Written
<m2-6-2-pharmacology-written-summary>
Summary
<leaf>
</leaf>
</m2-6-2-pharmacology-written-summary>
2.6.3 Pharmacology Tabulated <m2-6-3-pharmacology-tabulated-summary>
Summary
<leaf>
</leaf>
</m2-6-3-pharmacology-tabulated-summary>
2.6.4 Pharmacokinetics Written <m2-6-4-pharmacokinetics-written-summary>
Summary
<leaf>
</leaf>
</m2-6-4-pharmacokinetics-written-summary>
2.6.5 Pharmacokinetics
<m2-6-5-pharmacokinetics-tabulated-summary>
Tabulated Summary
<leaf>
</leaf>
</m2-6-5-pharmacokinetics-tabulated-summary>
2.6.6 Toxicology Written
<m2-6-6-toxicology-written-summary>
Summary
<leaf>
</leaf>
</m2-6-6-toxicology-written-summary>
2.6.7 Toxicology Tabulated
<m2-6-7-toxicology-tabulated-summary>
Summary
<leaf>
</leaf>
</m2-6-7-toxicology-tabulated-summary>
End NWTS
</m2-6-nonclinical-written-and-tabulated-summaries>
Module 2: Clinical Overview
<m2-5-clinical-overview>
<leaf>
</leaf>
</m2-5-clinical-overview>
Module 2: Clinical Summary (CS)
<m2-7-clinical-summary>
2.7.1 Summary of
<m2-7-1-summary-of-biopharmaceutic-studies-andBiopharmaceutic
associated-analytical-methods>
Studies and Associated
<leaf>
Analytical Methods
</leaf>
</m2-7-1-summary-of-biopharmaceutic-studies-andassociated-analytical-methods>
2.7.2 Summary of Clinical
<m2-7-2-summary-of-clinical-pharmacology-studies>
Pharmacology Studies
</m2-7-2-summary-of-clinical-pharmacology-studies>
2.7.3 Summary of Clinical
<m2-7-3-summary-of-clinical-efficacy
Efficacy
indication="">
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Module 2 CTD Heading

2.7.4 Summary of Clinical


Safety
2.7.5 References

2.7.6 Synopses of Individual


Studies
End CS
End CTD Summaries

heading element (leaf element abbreviated for clarity)


<leaf>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>4
<m2-7-4-summary-of-clinical-safety>
<leaf>
</leaf>
</m2-7-4-summary-of-clinical-safety>
<m2-7-5-literature-references>
<leaf>
</leaf>
</m2-7-5-literature-references>
<m2-7-6-synopses-of-individual-studies>
<leaf>
</leaf>
</m2-7-6-synopses-of-individual-studies>
</m2-7-clinical-summary>
</m2-common-technical-document-summaries>

2. Attribute Values for Module 2 heading Elements


The heading element for the Summary of Clinical Efficacy heading, <m2-7-3-summary-ofclinical-efficacy>, has an attribute called indication. The purpose of the indication attribute is to
provide human readable abbreviation of the clinical indication being summarized under this
heading. If there is more than one indication for which a Summary of Clinical Efficacy (SCE) is
being submitted, you should create an additional SCE heading element for each indication. Each
SCE heading element should be the same except for the unique indication attribute value and
leaf content. An example of two indication attributes and their values within two SCE heading
elements is provided:
<m2-common-technical-document-summaries>
<m2-7-clinical-summary>
<m2-7-3-summary-of-clinical-efficacy indication="pneumonia">
<leaf></leaf>5
</m2-7-3-summary-of-clinical-efficacy>
<m2-7-3-summary-of-clinical-efficacy indication="sepsis">
<leaf></leaf>6
</m2-7-3-summary-of-clinical-efficacy>
</m2-7-clinical-summary>
</m2-common-technical-document-summaries>

See the description of element attributes after this table


Leaf element abbreviated for clarity.
6
Leaf element abbreviated for clarity.
5

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The eCTD Backbone File Specification for Modules 2 through 5


You should provide an indication attribute value for every SCE heading element. There is no
limit to the number of SCE heading elements.
B. Heading elements and attributes for Module 3
This section includes the heading elements and attribution values relevant to module 3.
1. Module 3 heading elements
The module 3 heading elements are summarized in the following table. In some cases, the CTD
may describe more subheadings than appear on this table. Those subheadings should be used as
bookmarks within the individual document. Both the start tag and end tag for each heading
element are provided. If there are one or more subheadings for the heading, the corresponding
element end tag will occur on the table row below the last relevant subheading. The leaf element
is included to show where the leaf elements should be placed. The details for the leaf elements
are not shown on this table to keep it clearer. The leaf elements should only occur where
indicated in this table. A heading element may contain any number of leaf elements. If no
documents are submitted for a heading, you should omit the element for that heading in the
eCTD backbone file.
Module 3 CTD Heading
Module: 3 Quality
3.2 Body of Data
3.2.S Drug Substance
Name
Manufacturer
3.2.S.1 General Information
3.2.S.1.1 Nomenclature

3.2.S.1.2 Structure

3.2.S.1.3 General Properties

End General Information


3.2.S.2 Manufacture

eCTD Element
<m3-quality>
<m3-2-body-of-data>
<m3-2-s-drug-substance
substance=""
manufacturer="">7
<m3-2-s-1-general-information>
<m3-2-s-1-1-nomenclature>
<leaf>
</leaf>
</m3-2-s-1-1-nomenclature>
<m3-2-s-1-2-structure>
<leaf>
</leaf>
</m3-2-s-1-2-structure>
<m3-2-s-1-3-general-properties>
<leaf>
</leaf>
</m3-2-s-1-3-general-properties>
</m3-2-s-1-general-information>
<m3-2-s-2-manufacture>

See the description of element attributes after this table.

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Module 3 CTD Heading
3.2.S.2.1 Manufacturers

3.2.S.2.2 Description of
Manufacturing

3.2.S.2.3 Control of Materials

3.2.S.2.4 Controls of Critical


Steps and Intermediates

3.2.S.2.5 Process Validation


and/or Evaluation
3.2.S.2.6 Manufacturing Process
Development
End Manufacture
3.2.S.3 Characterization
3.2.S.3.1 Elucidation of Structure
and other Characteristics

3.2.S.3.2 Impurities

End Characterization
3.2.S.4 Control of Drug Substance

Version 1.1

eCTD Element
<m3-2-s-2-1-manufacturer>
<leaf>
</leaf>
</m3-2-s-2-1-manufacturer>
<m3-2-s-2-2-description-of-manufacturing-process-andprocess-controls>
<leaf>
</leaf>
</m3-2-s-2-2-description-of-manufacturing-process-andprocess-controls>
<m3-2-s-2-3-control-of-materials>
<leaf>
</leaf>
</m3-2-s-2-3-control-of-materials>
<m3-2-s-2-4-controls-of-critical-steps-andintermediates>
<leaf>
</leaf>
</m3-2-s-2-4-controls-of-critical-steps-andintermediates>
<m3-2-s-2-5-process-validation-and-or-evaluation>
<leaf>
</leaf>
</m3-2-s-2-5-process-validation-and-or-evaluation>
<m3-2-s-2-6-manufacturing-process-development>
<leaf>
</leaf>
</m3-2-s-2-6-manufacturing-process-development>
</m3-2-s-2-manufacture>
<m3-2-s-3-characterisation>
<m3-2-s-3-1-elucidation-of-structure-and-othercharacteristics>
<leaf>
</leaf>
</m3-2-s-3-1-elucidation-of-structure-and-othercharacteristics>
<m3-2-s-3-2-impurities>
<leaf>
</leaf>
</m3-2-s-3-2-impurities>
</m3-2-s-3-characterisation>
<m3-2-s-4-control-of-drug-substance>

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The eCTD Backbone File Specification for Modules 2 through 5


Module 3 CTD Heading
3.2.S.4.1 Specification

3.2.S.4.2 Analytical Procedures

3.2.S.4.3 Validation of Analytical


Procedures
3.2.S.4.4 Batch Analyses

3.2.S.4.5 Justification of
Specification
End Control of Drug Substance
3.2.S.5 Reference Standards or
Materials
3.2.S.6 Container Closure System

3.2.S.7 Stability
3.2.S.7.1 Stability Summary and
Conclusions
3.2.S.7.2 Postapproval Stability
Protocol and Stability
Commitment

3.2.S.7.3 Stability Data

End Stability
Version 1.1

eCTD Element
<m3-2-s-4-1-specification>
<leaf>
</leaf>
</m3-2-s-4-1-specification>
<m3-2-s-4-2-analytical-procedures>
<leaf>
</leaf>
</m3-2-s-4-2-analytical-procedures>
<m3-2-s-4-3-validation-of-analytical-procedures>
<leaf>
</leaf>
</m3-2-s-4-3-validation-of-analytical-procedures>
<m3-2-s-4-4-batch-analyses>
<leaf>
</leaf>
</m3-2-s-4-4-batch-analyses>
<m3-2-s-4-5-justification-of-specification>
<leaf>
</leaf>
</m3-2-s-4-5-justification-of-specification>
</m3-2-s-4-control-of-drug-substance>
<m3-2-s-5-reference-standards-or-materials>
<leaf>
</leaf>
</m3-2-s-5-reference-standards-or-materials>
<m3-2-s-6-container-closure-system>
<leaf>
</leaf>
</m3-2-s-6-container-closure-system>
<m3-2-s-7-stability>
<m3-2-s-7-1-stability-summary-and-conclusions>
<leaf>
</leaf>
</m3-2-s-7-1-stability-summary-and-conclusions>
<m3-2-s-7-2-post-approval-stability-protocol-andstability-commitment>
<leaf>
</leaf>
</m3-2-s-7-2-post-approval-stability-protocol-andstability-commitment>
<m3-2-s-7-3-stability-data>
<leaf>
</leaf>
</m3-2-s-7-3-stability-data>
</m3-2-s-7-stability>
16

The eCTD Backbone File Specification for Modules 2 through 5


Module 3 CTD Heading
End Drug Substance
3.2.P Drug Product
Name
Dosage Form
Manufacturer
3.2.P.1 Description and Composition
of the Drug Product

eCTD Element
</m3-2-s-drug-substance>
<m3-2-p-drug-product
product-name=""
dosageform=""
manufacturer="">8
<m3-2-p-1-description-and-composition-of-the-drugproduct>
</m3-2-p-1-description-and-composition-of-the-drugproduct>
3.2.P.2 Pharmaceutical Development <m3-2-p-2-pharmaceutical-development>
<leaf>
</leaf>
</m3-2-p-2-pharmaceutical-development>
3.2.P.3 Manufacture
<m3-2-p-3-manufacture>
3.2.P.3.1 Manufacturers
<m3-2-p-3-1-manufacturers>
<leaf>
</leaf>
</m3-2-p-3-1-manufacturers>
3.2.P.3.2 Batch Formula
<m3-2-p-3-2-batch-formula>
<leaf>
</leaf>
</m3-2-p-3-2-batch-formula>
3.2.P.3.3 Description of
<m3-2-p-3-3-description-of-manufacturing-process-andManufacturing Process and
process-controls>
Process Controls
<leaf>
</leaf>
</m3-2-p-3-3-description-of-manufacturing-process-andprocess-controls>
3.2.P.3.4 Controls of Critical
<m3-2-p-3-4-controls-of-critical-steps-andSteps and Intermediates
intermediates>
<leaf>
</leaf>
</m3-2-p-3-4-controls-of-critical-steps-andintermediates>
3.2.P.3.5 Process Validation
<m3-2-p-3-5-process-validation-and-or-evaluation>
and/or Evaluation
<leaf>
</leaf>
</m3-2-p-3-5-process-validation-and-or-evaluation>
End Manufacture
</m3-2-p-3-manufacture>
3.2.P.4 Control of Excipients
<m3-2-p-4-control-of-excipients
excipient="">9

8
9

See the description of element attributes after this table.


See the description of element attributes after this table.

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Module 3 CTD Heading
3.2.P.4.1 Specifications

3.2.P.4.2 Analytical Procedures

3.2.P.4.3 Validation of Analytical


Procedures
3.2.P.4.4 Justification of
Specifications
3.2.P.4.5 Excipients of Human or
Animal Origin
3.2.P.4.6 Novel Excipients

End Control of Excipients


3.2.P. 5 Control of Drug Product
3.2.P.5.1 Specifications

3.2.P.5.2 Analytical Procedures

3.2.P.5.3 Validation of Analytical


Procedures
3.2.P.5.4 Batch Analyses

Version 1.1

eCTD Element
<m3-2-p-4-1-specifications>
<leaf>
</leaf>
</m3-2-p-4-1-specifications>
<m3-2-p-4-2-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-4-2-analytical-procedures>
<m3-2-p-4-3-validation-of-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-4-3-validation-of-analytical-procedures>
<m3-2-p-4-4-justification-of-specifications>
<leaf>
</leaf>
</m3-2-p-4-4-justification-of-specifications>
<m3-2-p-4-5-excipients-of-human-or-animal-origin>
<leaf>
</leaf>
</m3-2-p-4-5-excipients-of-human-or-animal-origin>
<m3-2-p-4-6-novel-excipients>
<leaf>
</leaf>
</m3-2-p-4-6-novel-excipients>
</m3-2-p-4-control-of-excipients>
<m3-2-p-5-control-of-drug-product>
<m3-2-p-5-1-specifications>
<leaf>
</leaf>
</m3-2-p-5-1-specifications>
<m3-2-p-5-2-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-5-2-analytical-procedures>
<m3-2-p-5-3-validation-of-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-5-3-validation-of-analytical-procedures>
<m3-2-p-5-4-batch-analyses>
<leaf>
</leaf>
</m3-2-p-5-4-batch-analyses>

18

The eCTD Backbone File Specification for Modules 2 through 5


Module 3 CTD Heading
3.2.P.5.5 Characterization of
Impurities
3.2.P.5.6 Justification of
Specifications
End Control of Drug Product
3.2.P.6 Reference Standards or
Materials
3.2.P.7 Container Closure System

3.2.P.8 Stability
3.2.P.8.1 Stability Summary and
Conclusion
3.2.P.8.2 Postapproval Stability
Protocol and Stability
Commitment

3.2.P.8.3 Stability Data

End Stability
End Drug Product
3.2.A APPENDICES
3.2.A.1 Facilities and Equipment

10

eCTD Element
<m3-2-p-5-5-characterisation-of-impurities>
<leaf>
</leaf>
</m3-2-p-5-5-characterisation-of-impurities>
<m3-2-p-5-6-justification-of-specifications>
<leaf>
</leaf>
</m3-2-p-5-6-justification-of-specifications>
</m3-2-p-5-control-of-drug-product>
<m3-2-p-6-reference-standards-or-materials>
<leaf>
</leaf>
</m3-2-p-6-reference-standards-or-materials>
<m3-2-p-7-container-closure-system>
<leaf>
</leaf>
</m3-2-p-7-container-closure-system>
<m3-2-p-8-stability>
<m3-2-p-8-1-stability-summary-and-conclusion>
<leaf>
</leaf>
</m3-2-p-8-1-stability-summary-and-conclusion>
<m3-2-p-8-2-post-approval-stability-protocol-andstability-commitment>
<leaf>
</leaf>
</m3-2-p-8-2-post-approval-stability-protocol-andstability-commitment>
<m3-2-p-8-3-stability-data>
<leaf>
</leaf>
</m3-2-p-8-3-stability-data>
</m3-2-p-8-stability>
</m3-2-p-drug-product>
<m3-2-a-appendices>
<m3-2-a-1-facilities-and-equipment
manufacturer=""
substance=""
dosageform=""
product-name="">10
<leaf>
</leaf>
</m3-2-a-1-facilities-and-equipment

See the description of element attributes after this table.

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Module 3 CTD Heading
3.2.A.2 Adventitious Agents
Safety Evaluation

3.2.A.3 Novel Excipients

End Appendices
3.2.R REGIONAL INFORMATION

End Body of Data


3.3 LITERATURE REFERENCES

End Quality

eCTD Element
<m3-2-a-2-adventitious-agents-safety-evaluation
manufacturer=""
substance=""
dosageform=""
product-name="">11
<leaf>
</leaf>
</m3-2-a-2-adventitious-agents-safety-evaluation>
<m3-2-a-3-excipients>
<leaf>
</leaf>
</m3-2-a-3-excipients>
</m3-2-a-appendices>
<m3-2-r-regional-information>
<leaf>
</leaf>
</m3-2-r-regional-information>
</m3-2-body-of-data>
<m3-3-literature-references>
<leaf>
</leaf>
</m3-3-literature-references>
</m3-quality>

2. Attribute Values for Module 3 heading Elements


Five of the Module 3 heading elements have attributes. You should provide attribute values for
each of these attributes.
a) Drug substance attributes
The heading element for the Drug Substance heading, <m3-2-s-drug-substance>, has two
attributes, substance and manufacturer. The purpose of these attributes is to provide text to
indicate the drug substance name or names and organizational headings for different
manufacturers of the drug substance. These situations are more fully described in the Guidance
for Industry M4: The CTD-- Quality document. An example of two Drug Substance heading
elements for different manufacturers of the same drug substance is provided:
<m3-quality>
<m3-2-body-of-data>
<m3-2-s-drug-substance
substance="Cure All USP"
11

See the description of element attributes after this table.

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manufacturer="China-DMF-999999">
<leaf></leaf>12
</m3-2-s-drug-substance>
<m3-2-s-drug-substance
substance=" Cure All USP "
manufacturer="Louisiana">
<leaf></leaf>13
</m3-2-s-drug-substance>
</m3-2-body-of-data >
</m3-quality >
You should provide substance and manufacturer attribute values for every Drug Substance
heading element. There is no limit to the number of Drug Substance heading elements. There is
no limit to the number of leaf elements the Drug Substance heading element can contain.
b) Drug product attributes
The heading element for the Drug Product heading, <m3-2-p-drug-product>, has three attributes,
product-name, dosageform and manufacturer. The purpose of these attributes is to provide text
to indicate the drug product names and organizational headings for different dosage forms and
the organizational headings for different manufacturers of the drug product. These situations are
more fully described in the Guidance for Industry M4: The CTD-- Quality document. An
example of two Drug Product heading elements for different manufacturers of the same dosage
form and the same product name is provided:
<m3-quality>
<m3-2-body-of-data>
<m3-2-p-drug-product
product-name="Cure All"
dosageform="Injection"
manufacturer="China Plant 1 DMF-0000001">
<leaf></leaf>14
</ m3-2-p-drug-product >
<m3-2-p-drug-product
product-name="Cure All"
dosageform="Injection"
manufacturer="Puerto Rico Internal-Plant-#2">
<leaf></leaf>15
</m3-2-p-drug-product>
</ m3-2-body-of-data >
</m3-quality >
12

Leaf element abbreviated for clarity.


Leaf element abbreviated for clarity.
14
Leaf element abbreviated for clarity.
15
Leaf element abbreviated for clarity.
13

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The eCTD Backbone File Specification for Modules 2 through 5

You should provide product-name, dosageform and manufacturer attribute values for every Drug
Product heading element. There is no limit to the number of Drug Product heading elements.
There is no limit to the number of leaf elements the Drug Product heading element can contain.
c) Excipient Attribute
The heading element for Control of Excipients, <m3-2-p-4-control-of-excipients>, has an
attribute called excipient. The purpose of the excipient attribute is to provide text to indicate the
excipient for which information is being provided. If there is more than one excipient, you
should create an additional Control of Excipients heading element for each excipient. An
example of a Control of Excipients element with its excipient attribute is provided:
<m3-quality>
<m3-2-p-drug-product
product-name="Cure All"
dosageform="Injection"
manufacturer="China Plant 1 DMF-0000001">
<m3-2-p-4-control-of-excipients
excipient="corn syrup">
<m3-2-p-4-1-specifications>
<leaf></leaf>16
</m3-2-p-4-1-specifications>
<m3-2-p-4-2-analytical-procedures>
<leaf></leaf>17
</m3-2-p-4-2-analytical-procedures>
<m3-2-p-4-4-justification-of-specifications>
<leaf></leaf>18
</m3-2-p-4-4-justification-of-specifications>
</m3-2-p-4-control-of-excipients>
</m3-2-p-drug-product>
</m3-quality>
You should provide an excipient attribute value for every Control of Excipients heading element.
There is no limit to the number of Control of Excipients heading elements. There is no limit to
the number of leaf elements the Control of Excipients heading element can contain.
d) Attributes for Appendix Elements
The heading elements for the Facilities and Equipment heading, <m3-2-a-1-facilities-andequipment> and for the Adventitious Agents Safety Evaluation heading, <m3-2-a-216

Leaf element abbreviated for clarity.


Leaf element abbreviated for clarity.
18
Leaf element abbreviated for clarity.
17

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The eCTD Backbone File Specification for Modules 2 through 5


adventitious-agents-safety-evaluation>, have two and three attributes, respectively, from the
following 4 possibilities: manufacturer, substance, dosageform and product-name. The purpose
of these attributes is to provide text to correlate the appendix with the manufacturer, drug
substance, dosage form and drug product name. These situations are more fully described in the
Guidance for Industry M4: The CTD-- Quality document. An example of the Facilities and
Equipment heading and the Adventitious Agents Safety Evaluation heading elements with their
attributes is provided:
<m3-quality>
<m3-2-a-appendices>
<m3-2-a-1-facilities-and-equipment
manufacturer=" China Plant 1 DMF-0000001"
product-name="Cure All">
<leaf></leaf>19
</m3-2-a-1-facilities-and-equipment
<m3-2-a-2-adventitious-agents-safety-evaluation
manufacturer="Animal Extractions Inc"
substance="Parts Substrate"
dosageform="Injection">
<leaf></leaf>20
</m3-2-a-2-adventitious-agents-safety-evaluation>
</m3-2-a-appendices>
</m3-quality>
You should provide a manufacturer, and substance or product-name attribute and value for every
Facilities and Equipment heading element and manufacturer, dosageform and substance or
product-name, for every Adventitious Agents Safety Evaluation heading element. There is no
limit to the number of Facilities and Equipment heading and the Adventitious Agents Safety
Evaluation heading elements. There is no limit to the number of leaf elements the Facilities and
Equipment and the Adventitious Agents Safety Evaluation heading elements can contain.
C. Heading elements and attributes for module 4
This section includes the heading and attributes elements relevant to module 4.
1. Heading elements
The module 4 heading elements are summarized in the following table. In some cases, the CTD
may describe more subheadings than appear on this table. Those subheadings should be used as
bookmarks within the individual document. Both the start tag and end tag for each heading
element are provided. If there are one or more subheadings for the heading, the corresponding
element end tag will occur on the table row below the last relevant subheading. The leaf element
is included to show where the leaf elements should be placed. The details for the leaf elements
19
20

Leaf element abbreviated for clarity.


Leaf element abbreviated for clarity.

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The eCTD Backbone File Specification for Modules 2 through 5


are not shown on this table to keep it clearer. The leaf elements should only occur where
indicated in this table. A heading element may contain any number of leaf elements. If no
documents are submitted for a heading, you should omit the element for that heading in the
eCTD backbone file.
Module 4 CTD Heading
Module 4: Nonclinical Study Reports
4.2 Study Reports
4.2.1 Pharmacology
4.2.1.1 Primary Pharmacodynamics

4.2.1.2 Secondary
Pharmacodynamics
4.2.1.3 Safety Pharmacology

4.2.1.4 Pharmacodynamic Drug


Interactions
End Pharmacology
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and
Validation Reports

4.2.2.2 Absorption

4.2.2.3 Distribution

4.2.2.4 Metabolism

Version 1.1

eCTD Element
<m4-nonclinical-study-reports>
<m4-2-study-reports>
<m4-2-1-pharmacology>
<m4-2-1-1-primary-pharmacodynamics>
<leaf>
</leaf>
</m4-2-1-1-primary-pharmacodynamics>
<m4-2-1-2-secondary-pharmacodynamics>
<leaf>
</leaf>
</m4-2-1-2-secondary-pharmacodynamics>
<m4-2-1-3-safety-pharmacology>
<leaf>
</leaf>
</m4-2-1-3-safety-pharmacology>
<m4-2-1-4-pharmacodynamic-drug-interactions>
<leaf>
</leaf>
</m4-2-1-4-pharmacodynamic-drug-interactions>
</m4-2-1-pharmacology>
<m4-2-2-pharmacokinetics>
<m4-2-2-1-analytical-methods-and-validationreports>
<leaf>
</leaf>
</m4-2-2-1-analytical-methods-and-validationreports>
<m4-2-2-2-absorption>
<leaf>
</leaf>
</m4-2-2-2-absorption>
<m4-2-2-3-distribution>
<leaf>
</leaf>
</m4-2-2-3-distribution>
<m4-2-2-4-metabolism>
<leaf>
</leaf>
</m4-2-2-4-metabolism>

24

The eCTD Backbone File Specification for Modules 2 through 5


Module 4 CTD Heading
4.2.2.5 Excretion

4.2.2.6 Pharmacokinetic Drug


Interactions
4.2.2.7 Other Pharmacokinetic
Studies
End Pharmacokinetics
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity

4.2.3.2 Repeat-Dose Toxicity

4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro

4.2.3.3.2 In vivo

End Genotoxicity
4.2.3.4 Carcinogenicity
4.2.3.4.1 Long-term studies

4.2.3.4.2 Short- or medium-term


studies

Version 1.1

eCTD Element
<m4-2-2-5-excretion>
<leaf>
</leaf>
</m4-2-2-5-excretion>
<m4-2-2-6-pharmacokinetic-drug-interactions>
<leaf>
</leaf>
</m4-2-2-6-pharmacokinetic-drug-interactions>
<m4-2-2-7-other-pharmacokinetic-studies>
<leaf>
</leaf>
</m4-2-2-7-other-pharmacokinetic-studies>
</m4-2-2-pharmacokinetics>
<m4-2-3-toxicology>
<m4-2-3-1-single-dose-toxicity>
<leaf>
</leaf>
</m4-2-3-1-single-dose-toxicity>
<m4-2-3-2-repeat-dose-toxicity>
<leaf>
</leaf>
</m4-2-3-2-repeat-dose-toxicity>
<m4-2-3-3-genotoxicity>
<leaf>
</leaf>
<m4-2-3-3-1-in-vitro>
<leaf>
</leaf>
</m4-2-3-3-1-in-vitro>
<m4-2-3-3-2-in-vivo>
<leaf>
</leaf>
</m4-2-3-3-2-in-vivo>
</m4-2-3-3-genotoxicity>
<m4-2-3-4-carcinogenicity>
<m4-2-3-4-1-long-term-studies>
<leaf>
</leaf>
</m4-2-3-4-1-long-term-studies>
<m4-2-3-4-2-short-or-medium-term-studies>
<leaf>
</leaf>
</m4-2-3-4-2-short-or-medium-term-studies>

25

The eCTD Backbone File Specification for Modules 2 through 5


Module 4 CTD Heading
4.2.3.4.3 Other studies

End Carcinogenicity
4.2.3.5 Reproductive and
Developmental Toxicity
4.2.3.5.1 Fertility and early
embryonic development

4.2.3.5.2 Embryofetal
development
4.2.3.5.3 Prenatal and postnatal
development, including maternal
function

4.2.3.5.4 Studies in which the


offspring

End Reproductive Toxicology


4.2.3.6. Local Tolerance

4.2.3.7. Other Toxicity Studies


4.2.3.7.1 Antigenicity

Version 1.1

eCTD Element
<m4-2-3-4-3-other-studies>
<leaf>
</leaf>
</m4-2-3-4-3-other-studies>
</m4-2-3-4-carcinogenicity>
<m4-2-3-5-reproductive-and-developmentaltoxicity>
<m4-2-3-5-1-fertility-and-early-embryonicdevelopment>
<leaf>
</leaf>
</m4-2-3-5-1-fertility-and-early-embryonicdevelopment>
<m4-2-3-5-2-embryo-fetal-development>
<leaf>
</leaf>
</m4-2-3-5-2-embryo-fetal-development>
<m4-2-3-5-3-prenatal-and-postnataldevelopment-including-maternal-function>
<leaf>
</leaf>
</m4-2-3-5-3-prenatal-and-postnataldevelopment-including-maternal-function>
<m4-2-3-5-4-studies-in-which-the-offspringjuvenile-animals-are-dosed-and-or-furtherevaluated>
<leaf>
</leaf>
</m4-2-3-5-4-studies-in-which-the-offspringjuvenile-animals-are-dosed-and-or-furtherevaluated>
</m4-2-3-5-reproductive-and-developmentaltoxicity>
<m4-2-3-6-local-tolerance>
<leaf>
</leaf>
</m4-2-3-6-local-tolerance>
<m4-2-3-7-other-toxicity-studies>
<m4-2-3-7-1-antigenicity>
<leaf>
</leaf>
</m4-2-3-7-1-antigenicity>

26

The eCTD Backbone File Specification for Modules 2 through 5


Module 4 CTD Heading
4.2.3.7.2 Immunotoxicity

4.2.3.7.3 Mechanistic studies

4.2.3.7.4 Dependence

4.2.3.7.5 Metabolites

4.2.3.7.6 Impurities

4.2.3.7.7 Other

End Other
End Toxicology
End Study Reports
4.3 Literature References

End Nonclinical

eCTD Element
<m4-2-3-7-2-immunotoxicity>
<leaf>
</leaf>
</m4-2-3-7-2-immunotoxicity>
<m4-2-3-7-3-mechanistic-studies>
<leaf>
</leaf>
</m4-2-3-7-3-mechanistic-studies>
<m4-2-3-7-4-dependence>
<leaf>
</leaf>
</m4-2-3-7-4-dependence>
<m4-2-3-7-5-metabolites>
<leaf>
</leaf>
</m4-2-3-7-5-metabolites>
<m4-2-3-7-6-impurities>
<leaf>
</leaf>
</m4-2-3-7-6-impurities>
<m4-2-3-7-7-other>
<leaf>
</leaf>
</m4-2-3-7-7-other>
</m4-2-3-7-other-toxicity-studies>
</m4-2-3-toxicology>
</m4-2-study-reports>
<m4-3-literature-references>
<leaf>
</leaf>
</m4-3-literature-references>
</m4-nonclinical-study-reports>

An example of the elements used to organize the leaf element for the Embryo Fetal Development
Toxicology heading document is provided:
<m4-nonclinical-study-reports>
<m4-2-study-reports>
<m4-2-3-toxicology>
<m4-2-3-5-reproductive-and-developmental-toxicity>
<m4-2-3-5-2-embryo-fetal-development>
<leaf></leaf>21
</m4-2-3-5-2-embryo-fetal-development>
21

Leaf element abbreviated for clarity.

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27

The eCTD Backbone File Specification for Modules 2 through 5


</m4-2-3-5-reproductive-and-developmental-toxicity>
</m4-2-3-toxicology>
</m4-2-study-reports>
</m4-nonclinical-study-reports>
The number of leaf elements that the heading elements can contain is not limited.
2. Attributes for Module 4 heading elements
There are no attributes for Module 4 heading elements.
D. Heading elements and attributes for module 5
This section includes the heading elements and attributes relevant to module 5.
1. Module 5 Heading element
The module 5 heading elements are summarized in the following table. In some cases, the CTD
may describe more subheadings than appear on this table. Those subheadings should be used as
bookmarks within the individual document. Both the start tag and end tag for each heading
element are provided. If there are one or more subheadings for the heading, the corresponding
element end tag will occur on the table row below the last relevant subheading. The leaf element
is included to show where the leaf elements should be placed. The details for the leaf elements
are not shown on this table to keep it clearer. The leaf elements should only occur where
indicated in this table. A heading element may contain any number of leaf elements. If no
documents are submitted for a heading, you should omit the element for that heading in the
eCTD backbone file.
Module 5 CTD Heading
Module 5: Clinical Study Reports
5.2 Tabular Listing Of All Clinical
Studies
5.3 Clinical Study Reports And
Related Information
5.3.1 Reports Of Biopharmaceutic
Studies
5.3.1.1 Bioavailability (BA) Study
Reports

Version 1.1

eCTD Element
<m5-clinical-study-reports>
<m5-2-tabular-listing-of-all-clinical-studies>
<leaf>
</leaf>
</m5-2-tabular-listing-of-all-clinical-studies>
<m5-3-clinical-study-reports>
<m5-3-1-reports-of-biopharmaceutic-studies >
<m5-3-1-1-bioavailability-study-reports>
<leaf>
</leaf>
</m5-3-1-1-bioavailability-study-reports>

28

The eCTD Backbone File Specification for Modules 2 through 5


Module 5 CTD Heading
5.3.1.2 Comparative BA And
Bioequivalence (BE) Study Reports

5.3.1.3 In Vitro-In Vivo Correlation


Study Reports

5.3.1.4 Reports Of Bioanalytical And


Analytical Methods For Human
Studies

End Biopharm
5.3.2 Reports Of Studies Pertinent To
Pharmacokinetics Using Human
Biomaterials
5.3.2.1 Plasma Protein Binding Study
Reports
5.3.2.2 Reports Of Hepatic
Metabolism And Drug Interaction
Studies

5.3.2.3 Reports Of Studies Using


Other Human Biomaterials

End Human Biomaterials


5.3.3 Reports Of Human
Pharmacokinetic (PK) Studies

Version 1.1

eCTD Element
<m5-3-1-2-comparative-ba-and-bioequivalencestudy-reports>
<leaf>
</leaf>
</m5-3-1-2-comparative-ba-and-bioequivalencestudy-reports>
<m5-3-1-3-in-vitro-in-vivo-correlation-studyreports>
<leaf>
</leaf>
</m5-3-1-3-in-vitro-in-vivo-correlation-studyreports>
<m5-3-1-4-reports-of-bioanalytical-and-analyticalmethods-for-human-studies>
<leaf>
</leaf>
</m5-3-1-4-reports-of-bioanalytical-and-analyticalmethods-for-human-studies>
</m5-3-1-reports-of-biopharmaceutic-studies>
<m5-3-2-reports-of-studies-pertinent-topharmacokinetics-using-human-biomaterials>
<m5-3-2-1-plasma-protein-binding-study-reports>
<leaf>
</leaf>
</m5-3-2-1-plasma-protein-binding-study-reports>
<m5-3-2-2-reports-of-hepatic-metabolism-and-druginteraction-studies>
<leaf>
</leaf>
</m5-3-2-2-reports-of-hepatic-metabolism-anddrug-interaction-studies>
<m5-3-2-3-reports-of-studies-using-other-humanbiomaterials>
<leaf>
</leaf>
</m5-3-2-3-reports-of-studies-using-other-humanbiomaterials>
</m5-3-2-reports-of-studies-pertinent-topharmacokinetics-using-human-biomaterials>
<m5-3-3-reports-of-human-pharmacokinetics-pkstudies>

29

The eCTD Backbone File Specification for Modules 2 through 5


Module 5 CTD Heading
5.3.3.1 Healthy Subject PK And Initial
Tolerability Study Reports

5.3.3.2 Patient PK And Initial


Tolerability Study Reports

5.3.3.3 Intrinsic Factor Pk Study


Reports
5.3.3.4 Extrinsic Factor Pk Study
Reports
5.3.3.5 Population Pk Study Reports

End PK
5.3.4 Reports Of Human
Pharmacodynamic (PD) Studies
5.3.4.1 Healthy Subject PD And
PK/PD Study Reports

5.3.4.2 Patient PD And PK/PD Study


Reports

5.3.5 Reports Of Efficacy And Safety


Studies

22

eCTD Element
<m5-3-3-1-healthy-subject-pk-and-initialtolerability-study-reports>
<leaf>
</leaf>
</m5-3-3-1-healthy-subject-pk-and-initialtolerability-study-reports>
<m5-3-3-2-patient-pk-and-initial-tolerability-studyreports>
<leaf>
</leaf>
</m5-3-3-2-patient-pk-and-initial-tolerability-studyreports>
<m5-3-3-3-intrinsic-factor-pk-study-reports>
<leaf>
</leaf>
</m5-3-3-3-intrinsic-factor-pk-study-reports>
<m5-3-3-4-extrinsic-factor-pk-study-reports>
<leaf>
</leaf>
</m5-3-3-4-extrinsic-factor-pk-study-reports>
<m5-3-3-5-population-pk-study-reports>
<leaf>
</leaf>
</m5-3-3-5-population-pk-study-reports>
</m5-3-3-reports-of-human-pharmacokinetics-pkstudies>
<m5-3-4-reports-of-human-pharmacodynamics-pdstudies>
<m5-3-4-1-healthy-subject-pd-and-pk-pd-studyreports>
<leaf>
</leaf>
</m5-3-4-1-healthy-subject-pd-and-pk-pd-studyreports>
<m5-3-4-2-patient-pd-and-pk-pd-study-reports>
<leaf>
</leaf>
</m5-3-4-2-patient-pd-and-pk-pd-study-reports>
</m5-3-4-reports-of-human-pharmacodynamics-pdstudies>
<m5-3-5-reports-of-efficacy-and-safety-studies
indication="">22

See the description of element attributes after this table.

Version 1.1

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The eCTD Backbone File Specification for Modules 2 through 5


Module 5 CTD Heading
5.3.5.1 Study Reports Of Controlled
Clinical Studies Pertinent To The
Claimed Indication

5.3.5.2 Study Reports Of Uncontrolled


Clinical Studies

5.3.5.3 Reports Of Analyses Of Data


From More Than One Study

5.3.5.4 Other Study Reports

End Efficacy and Safety


5.3.6 Reports Of Postmarketing
Experience
5.3.7 Case Report Forms and
Individual Patient Listings
5.4literature References

End Module 5

eCTD Element
<m5-3-5-1-study-reports-of-controlled-clinicalstudies-pertinent-to-the-claimed-indication>
<leaf>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinicalstudies-pertinent-to-the-claimed-indication>
<m5-3-5-2-study-reports-of-uncontrolled-clinicalstudies>
<leaf>
</leaf>
</m5-3-5-2-study-reports-of-uncontrolled-clinicalstudies>
<m5-3-5-3-reports-of-analyses-of-data-from-morethan-one-study>
<leaf>
</leaf>
</m5-3-5-3-reports-of-analyses-of-data-from-morethan-one-study>
<m5-3-5-4-other-study-reports>
<leaf>
</leaf>
</m5-3-5-4-other-study-reports>
</m5-3-5-reports-of-efficacy-and-safety-studies>
<m5-3-6-reports-of-postmarketing-experience>
<leaf>
</leaf>
</m5-3-6-reports-of-postmarketing-experience>
This heading is not used. The leaf for case report forms
and individual patient listings files are placed with the
appropriate study report using the Study Tagging File
<m5-4-literature-references>
<leaf>
</leaf>
</m5-4-literature-references>
<m5-clinical-study-reports>

2. Attribute for Module 5 heading elements


The heading element for the Reports of Efficacy And Safety Studies (ES) heading, <m5-3-5reports-of-efficacy-and-safety-studies >, has an attribute called indication. The purpose of the
indication attribute is to provide abbreviation of the clinical indication being summarized under
this heading. If there is more than one indication being claimed, you should create an additional
ES heading element for each indication. Each ES heading element should be the same except for
the unique indication attribute value and leaf content.

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31

The eCTD Backbone File Specification for Modules 2 through 5


The indication attribute for the ES heading element begins after the element name with a space
and the lowercase word indication. The value for the indication attribute is provided in a
statement that begins with the equal sign and quotation mark, (="), followed by the indication
attribute value and ending with a quotation mark. There should be no spaces in the indication
attribute's value statement. An example of two indication attributes and their values within two
ES heading elements is provided:
<m5-clinical-study-reports>
<m5-3-clinical-study-reports>
<m5-3-5-reports-of-efficacy-and-safety-studies
indication="pneumonia ">
<leaf></leaf>23
</m5-3-5-reports-of-efficacy-and-safety-studies >
<m5-3-5-reports-of-efficacy-and-safety-studies
indication="sepsis">
<leaf></leaf>24
</m5-3-5-reports-of-efficacy-and-safety-studies>
</m5-3-clinical-study-reports>
</m5-clinical-study-reports>
You should provide an indication attribute value for every ES heading element. There is no limit
to the number of ES heading elements. There is no limit to the number of leaf elements the ES
heading element can contain.

23
24

Leaf element abbreviated for clarity.


Leaf element abbreviated for clarity.

Version 1.1

32

SECTION 10

eCTD Backbone Files Study


Tagging Files

In order to help identify all of the files associated with a study, information is
needed on each document including the document title, subject matter (defined
by the headings under which the documents are located in the table of contents),
relationship to other documents, revision information, the location of the
document and information on the submission that included the document. This
document outlines the eCTD backbone files which include many of these
information items. However, the eCTD backbone files do not contain enough
information on the subject matter of several documents (e.g., study report
documents) to support certain regulatory business rules. This additional information
is provided in the STF. The complete structure and contents of the STF files is
presented in this section.

FDA Implementation of STF DTD v2.2

The eCTD Backbone Files Specification for Study Tagging Files


Revision History
Date
Version
Summary of Changes
2003-08-13
1.0
Original version
2004-03-09
1.1
Clarifications to the original version. Constrains from original version
including redundancy of information found in the index.xml file. Added
duration category and values. Added "other" as route of administration
value. Added new name attribute values for file tag element.
Versions between 1.1 and 2.6 have been unpublished drafts
2004-11-17
2.6
Provides specification for both Cumulative and Accumulative
Approaches for presentation of the Study Tagging Files (STF) with
more detailed examples showing index and stf file relationships.
Introduces ich-stf-v2-2.dtd, ich-stf-stylesheet-2-2.xsl and validvalues.xml.
2005-07-25
2.6
Posting for FDA. Removed Cumulative Approach for STF Lifecycle
and added US regional name attribute value individual-subject-datalisting. Also reinstituted "nonclinical-data" as US specific tag and
marked "pre-clinical-study-reports" as not used in US.

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FDA Implementation of STF DTD v2.2

THE SPECIFICATION FOR STUDY TAGGING FILES (STF) .........................................3


I.
II.
A.
B.
C.
III.
A.
B.
IV.
V.
A.
B.
VI.
A.
B.
VII.

ST ART AND STOP OF THE STF..................................................................................3


ST UDY-IDENTIFIER ELEMENT ..................................................................................4
Title Element..........................................................................................................4
study-id Element.....................................................................................................4
Category Element ...................................................................................................4
STUDY-DOCUMENT AND DOC-CONTENT ELEMENTS..............................................6
Property element ....................................................................................................6
File-tag element .....................................................................................................6
LIFECYCLE MANAGEMENT OF THE STUDY T AGGING FILE ....................................... 10
MODIFYING STF INFORMATION ..................................................................... 10
Changes to the STF Study Identifier Information .................................................... 11
Changes to STF Study Document Information ........................................................ 12
STUDY DATA MANAGEMENT OPTIONS ......................................................... 16
Distinguishing Time-Specific Analyses Within the Same Subsection of the CTD........ 17
Presenting Information from One Study in a Different Subsection of the CTD .......... 17
EXAMPLE SCENARIO .......................................................................................... 18

FDA Implementation of STF DTD v2.2

The Specification for Study Tagging Files (STF)


In order to help identify all of the files associated with a study, information is needed on
each document including the document title, subject matter (defined by the headings
under which the documents are located in the table of contents), relationship to other
documents (e.g., all documents for a specific study report are related to one another),
revision information (i.e., new, replace, deleted, append), the location of the document
and information on the submission that included the document. The eCTD backbone files
(e.g., index.xml and us-regional.xml) include many of those information items. However,
the eCTD backbone files do not contain enough information on the subject matter of
several documents (e.g., study report documents) to support certain regulatory business
rules. This additional information is provided in the STF.
An STF should be provided with the submission of any file, or group of files belonging to
a study in Modules 4 and 5. The STFs are required by the United States, but are optional
in Europe and Japan. The STF provides for additional heading elements and heading
attributes not currently provided by the eCTD DTD. In the STF, heading elements are
called file-tags and are included in the doc-content element. Heading attributes are
included in the study-identifier element.
Refer to regional guidance for information on STF applicability.
I. START AND STOP OF THE STF
The STF is an XML instance controlled by the ICH STF Document Type Definition
(DTD). The most recent DTD can be found on the ICH web site (www.ich.org). The
DTD should be placed in the dtd subfolder of the util folder. Version 2.2 of the STF DTD
introduces a revised stylesheet and an XML file named, valid-values.xml, which should
be in the style subfolder of the util folder. You should provide a separate STF for each
study in a submission. The name for the STF XML file should start with the term "stf-"
followed by the alphanumeric code used by the sponsor to unambiguously identify the
study (i.e., study-id described below) and followed by ".xml" to complete the file name.
For every submission to FDA that includes one or more files pertaining to a specific
study, you should provide an STF. You should place the STF for the specific study in the
module folder with the corresponding study files. You should place a leaf element in the
Module 4 or 5 eCTD index.xml file for each STF. In the corresponding Module 4 or 5
eCTD index.xml file, the STFs operation attribute should have a value of "new" for the
first STF for a specific study and "append" for any subsequent STF for the same study
(see "Lifecycle Management of the Study Tagging File". NOTE: STF files submitted to
the FDA should use the accumulative method of STF files even though the ICH version
of the Study Tagging File Specification v2.6 allows for both a cumulative and
accumulative approach). Use the study identifier (i.e., study-id described below) in the
title of the leaf. The STF should only include information on the study documents being
provided or modified within the new submission.
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FDA Implementation of STF DTD v2.2


The STF root element is ectd:study. The prolog part of the STF XML document and the
STF root element contain information about the following:
1. Version of XML being used
2. Type of characters that are allowed in the file
3. Location of the standards that control the organization of the STF
4. Indication that the file information is ended (end tag)
A sample of the root element and last line of the STF is provided below:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stfstylesheet-2-2.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtdversion="2.2" xmlns:xlink="http://www.w3.org/1999/xlink">
<!--All the elements will be provided after these elements and before the
last element closing tag named </ectd:study> -->
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on
the location where the STF instance is stored.
The STF root element contains two child elements: study-indentifier and studydocument.
II. STUDY-IDENTIFIER ELEMENT
Information describing the study is contained in the study-identifier element of the STF.
There are three elements contained in the study-identifier element: title, study-id, and
category.
A. Title Element
The title element provides the full title of the study, not the title of each individual
document. This is the name of the study and all related component study report files that
comprise the study report.
B. study-id Element
The study-id is the internal alphanumeric code used by the sponsor to unambiguously
identify this study.
C. Category Element
The category element provides an additional level of study organization not currently
provided by the eCTD DTD. This element is only relevant for studies provided in the
specific CTD sections cited below.
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FDA Implementation of STF DTD v2.2

4.2.3.1 Single dose toxicity (grouped by species and route of administration)


4.2.3.2 Repeat dose toxicity (grouped by species, route of administration, and
duration if applicable)
4.2.3.4.1 Long term [carcinogenicity] studies (grouped by species)
5.3.5.1 Study reports of controlled clinical studies pertinent to the claimed
indication (grouped by type of control)
Other studies do not call for any category elements. When appropriate, you should place
the category elements at the same level as the title and study-id elements. Each category
element has the attributes name and info-type. Attribute and element values should be
selected from the following table. The info-type attribute value should be "ich" for ICH
approved values or one of the regional values (e.g., "jp", "eu", "ca", "us") for region
specific values.
Category Element
Attributes and Values
name="species"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
name="route-of-admin"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
info-type="ich"
name="duration"
info-type="us"
info-type="us"
info-type="us"
name="type-of-control"
info-type="ich"
info-type="ich"
info-type="ich"
1

values for "category" element


content choices
mouse
rat
hamster
other-rodent
rabbit
dog
non-human-primate
other-non-rodent-mammal
non-mammals
oral
intravenous
intramuscular
intraperitoneal
subcutaneous
inhalation
topical
other (1see footnote)
short
medium
long
placebo
no-treatment
dose-response-without-placebo

Please consult the regional authorities before using "other".

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FDA Implementation of STF DTD v2.2


Category Element
Attributes and Values
info-type="ich"
info-type="ich"

values for "category" element


content choices
active-control-without-placebo
external

The following is an example of the use of the study-identifier elements in an STF for a
long term carcinogenicity study conducted in mice (species="mouse"):
<study-identifier>
<title>Long term carcinogenicity study</title>
<study-id>abc123xyz789</study-id>
<category name="species" info-type="ich" >mouse</category>
<category name="duration" info-type="us" >long</category>
</study-identifier>
III. STUDY-DOCUMENT AND DOC-CONTENT ELEMENTS
The study-document element2 contains information on the subject matter of each file that
is cited as part of the documentation for a study. The study-document element includes
the doc-content element. The doc-content element contains the property and file-tag
elements.
A. Property element
The property element is appropriate when files might need to be grouped by an applicant
provided value. Currently, this element is only to be used for site identification within a
study. For example, in the submission of case-report-forms, multiple forms originating
from the same study site should all be grouped by the study site property element.
Property Element
Attributes and Values
name="site-identifier"
info-type="us"

values for "property" element


content choices
User identified value for the site of the
study.

B. File-tag element
The file-tag element contains the attributes name and info-type. The text value of the filetag element's name attribute indicates the subject matter of the document. The value of
the file-tag name attribute should be selected from the values in the table below. For the
value of the info-type attribute, you should use "ich" if using an ICH value or one of the

The ICH STF Specification v2.6 includes a second element named block-content. However STF files
submitted to FDA should not utilize the block-content construct.

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FDA Implementation of STF DTD v2.2


regional values if the value is not defined in ICH. The table below shows the specified
name attribute values for the file-tag element.

name attribute values


for the file-tag element
(name=" ")
pre-clinical-study-report

infotype
value
ich

legacy-clinical-studyreport
synopsis
study-report-body
protocol-or-amendment
sample-case-report-form
iec-irb-consent-form-list

ich

list-descriptioninvestigator-site

ich

signatures-investigators

ich

list-patients-withbatches

ich

randomisation-scheme
audit-certificates-report

ich
ich

statistical-methodsinterim-analysis-plan
inter-laboratorystandardisationmethods-qualityassurance

ich

ich
ich
ich
ich
ich

ich

Content of Document
Pre-clinical study report ( 3see footnote)
NOTE: Do not use in STF submitted
to FDA4
Clinical study report submitted as one
file (*see footnote)
Study Report Synopsis
Study Report Body
Protocol and/amendments
Sample CRF
IEC and IRB and Consent Form
Listings
Description of Investigators and Sites
Signatures of principal or coordinating
investigator(s) or sponsors responsible
officer
Listing of patients receiving test
drug(s) from specified batch
Randomisation Scheme
Audit Certificates or similar
documentation
Documentation of statistical methods
and interim analysis plans
Documentation of Inter-laboratory
Standardization Methods and Quality
Assurance or similar documentation

E3
Reference

2
1,3 to 15
16.1.1
16.1.2
16.1.3
16.1.4
16.1.5
16.1.6
16.1.7
16.1.8
16.1.9
16.1.10

Refer to M4: Organisation Document, Granularity Annex for instructions on how to typically construct
study reports.
4

FDA does not use this STF tag value use the US specific "nonclinical-data" tag instead

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FDA Implementation of STF DTD v2.2


name attribute values
for the file-tag element
(name=" ")
publications-based-onstudy

infotype
value
ich

publications-referencedin-report
discontinued-patients
protocol-deviations

ich
ich
ich

patients-excluded-fromefficacy-analysis
demographic-data
compliance-and-drugconcentration-data
individual-efficacyresponse-data
adverse-event-listings
listing-individuallaboratorymeasurements-bypatient
case-report-forms

ich

available-on-request

ich

complete-patient-list

jp

serious-adverse-eventpatient-list

jp

adverse-event-patientlist

jp

abnormal-lab-valuespatient-list

jp

data-tabulation-dataset

us

ich
ich
ich
ich
ich

ich

Content of Document
Publications Based on the Study
Publications Referenced in the Study
Report
Discontinued Patients Listing
Protocol Deviation Listing
Patients Excluded from Efficacy
Analysis Listing
Demographic Data Listing
Compliance and/or Drug Concentration
Data Listing
Individual Efficacy Response Data
Listing
File contains Adverse Event Listings
Individual Laboratory Measurements
Listed by Patient
CRF for an individual subject. If you
are submitting in the US, you should
also provide a "property" element,
described below, with its "name"
attribute = "site-identifier" and its value
the site identification where the study
was performed.
A file listing documents available upon
request for a single study. Consult
regional guidance for use.
Complete patient list (Not used in STF
files submitted to FDA)
List of patients having serious adverse
events (Not used in STF files
submitted to FDA)
List of patients having adverse events
(Not used in STF files submitted to
FDA)
List of patients having abnormal lab
values (Not used in STF files submitted
to FDA)
Data tabulation dataset

E3
Reference

16.1.11
16.1.12
16.2.1
16.2.2
16.2.3
16.2.4
16.2.5
16.2.6
16.2.7
16.2.8

16.3

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FDA Implementation of STF DTD v2.2


infotype
value
us

name attribute values


for the file-tag element
(name=" ")
data-tabulation-datadefinition
data-listing-dataset
data-listing-datadefinition
analysis-dataset
analysis-program
analysis-data-definition
annotated-crf
ecg
image
subject-profiles

us
us
us
us
us
us
us

safety-report
antibacterial
special-pathogen

us
us
us

antiviral
iss

us
us

ise

us

pm-description

us

individual-subject-datalisting
nonclinical-data

us

us
us

Content of Document

E3
Reference

Data definitions for data tabulation


datasets
Data listing dataset
Data definitions for data listing datasets
Analysis datasets
Program file for analysis dataset
Data definition for analysis datasets
Annotated CRF for datasets
Annotated ECG waveform dataset
Image files
Subject profile. You should also
provide a "property" element, described
below, with its "name" attribute = "siteidentifier" and its value the site
identification where the study was
performed.
IND safety report
Antibacterial microbiology report
Special pathogens (e.g., fungi,
parasites, mycobacteria) and immune
modulator microbiology report
Antiviral microbiology report
Integrated analysis of safety
integrated summary of safety report
Integrated analysis of efficacy
integrated summary of efficacy report
Postmarketing periodic adverse event
drug experience report description
Individual-subject-data-listing

us

Data developed prior to module 5


clinical studies
Note: STF files submitted to the FDA should have file-tag values where the info-type
value is either ich or us.
When submitting in the US using a file-tag element with the name attribute value of
"subject-profile" or "case-report-forms", you should include a property element with the
name attribute value "site-identifier" and info-type value "us". The content of the property
element should be text that identifies the site.
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FDA Implementation of STF DTD v2.2


IV. LIFECYCLE MANAGEMENT OF THE STUDY TAGGING FILE
A. Cumulative Approach
FDA does not use the cumulative approach.
B. Accumulative Approach
In the accumulative approach, the applicant does not need to submit a complete
enumeration of the categories, file-tags and leaf ID values for the files that comprise the
Study Report with each submission. The STF would contain only the changes needed to
be made. When submitting the changes to the study report in the accumulation approach
the operation attribute value of the leaf entry for the subsequent STF should be "append".
The study-document information provided in this subsequent STF should only relate to
what is being modified in the current submission relative to the last submission for the
same STF.
For example, when an STF is being submitted in submission 0002 to provide
modifications (additions, deletions, corrections, etc) to information in the original STF
provided in submission 0000 with leaf ID m12345, the index.xml file of submission 0002
would contain the following leaf entry for the new STF:
<m4-2-1-1-primary-pharmacodynamics>
<leaf checksum-type="MD5"
version="STF Version 2.2" xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="append"
xlink:href="m4/42-stud-rep/421-pharmacol/4211-prim-pd/stf-jm-12-345.xml"
modified-file="../0000/index.xml#m12345"
ID="m42111">
<title>jm-12-345 Study Tagging File</title>
</leaf>
</m4-2-1-1-primary-pharmacodynamics>
Applicants should contact regional health authorities for the method to be used when
modifying STFs.
V. MODIFYING STF INFORMATION
During the lifecycle of an application, modifications to information contained in the STF
might be appropriate as the result of changes to the documentation cited in the STF,
changes to the categorization of information cited in the STF, or to correct errors in a
previous STF.
These modifications can be grouped as:
changes to the STF study-identifier information and
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FDA Implementation of STF DTD v2.2

changes to the STF study document information.

A. Changes to the STF Study Identifier Information


When an applicant determines that Study Identifier Information was incomplete or
incorrect (for example, a category element value was missing or erroneous in a
previously submitted STF), an STF XML file with the corrected category elements
should be submitted.
For example, an applicant submits an STF for a single-dose oral toxicity study (Study No.
JM-12-345) in serial 0001. The index.xml would contain a leaf entry for this file as
follows:
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="m4/42-stud-rep/423-tox/4231-single-dose-tox/stf-jm-12-345.xml"
ID="idm42111-0002">
<title>Study No. JM-12-345 STF</title>
</leaf>

The study-identifier section of this STF contains the following information:


<study-identifier>
<title>Single dose oral toxicity study in the mouse and dog</title>
<study-id>jm-12-345</study-id>
<category name = "species" info-type = "ich">rat</category>
<category name = "species" info-type = "ich">dog</category>
<category name = "route-of-admin" info-type = "ich">oral</category>
</study-identifier>

Clearly, the species identified by the species category tags are incorrect.
To correct this information, the applicant would submit a corrected STF in a subsequent
submission. The approach used to manage the STFs (Cumulative or Accumulative)
would determine the specific course of action.
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
In the Accumulative Approach, the information contained in subsequent STFs is
combined with the information contained in previous STFs to provide the reviewer the
cumulative view of all information. As there is no mechanism for comparing the
information contained in the study-identifier sections of the STFs submitted over time
using the Accumulative Approach, the information contained in the study-identifier
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FDA Implementation of STF DTD v2.2


section of the most recent STF will be deemed the most current. This applies to all
information contained in the study-identifier section of the STF (title, study-id and
category tags).
In order to correct the study-identifier information cited above for Study JM-12-345
using the Accumulative Approach, an additional STF would be submitted containing the
corrected information.
The index.xml in this subsequent submission (0002) would contain a leaf for the new
STF as follows:
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="append"
xlink:href="m4/42-stud-rep/423-tox/4231-single-dose-tox/stf-jm-12-345.xml"
modified-file="../0001/index.xml# idm42111-0002"
ID="a345">
<title>Study No. JM-12-345 STF</title>
</leaf>

If there was no additional documentation being provided for this study (and thus the
purpose of this STF is solely to correct the erroneous study-identifier information), the
STF would contain the following:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../util/style/ich-stf-stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Single dose oral toxicity study in the mouse and dog</title>
<study-id>jm-12-345</study-id>
<category name="species" info-type="ich">mouse</category>
<category name="species" info-type="ich">dog</category>
<category name="route-of-admin" info-type="ich">oral</category>
</study-identifier>
<study-document/>
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.
Note: The entire study-identifier block should be resubmitted containing all the category
values. The <study-document/> indicates that no additional file-tags are being provided and
is required since the study-document element is a mandatory element.

B. Changes to STF Study Document Information


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FDA Implementation of STF DTD v2.2


During the lifecycle of an application, modifications to the Study Document Information
contained in the STF might be required as a result of changes to the documentation cited
in the STF, changes to the categorization of documents cited in the STF, or to correct
errors in a previous STF.
These modifications can be grouped as:
1. Adding new files to an existing STF.
2. Replacing files cited by an existing STF,
3. Deleting files cited in an existing STF, and
4. Correcting file-tag values of files cited in an existing STF.
1. Adding New Files to an Existing STF
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
Using the Accumulative Approach, the applicant should submit an STF referencing only
the study related files provided in the current submission.
The index.xml for this submission should contain leaf entries for each new file being
provided as well as a leaf for the STF. The leaf of this STF should be submitted with the
append operation and modify the original STF for the study.
2. Replacing Files Cited by an Existing STF
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
Using the Accumulative Approach, the applicant should submit an STF referencing only
the study-related files provided in the current submission.
The index.xml for this submission should contain leaf entries for each new file being
provided as well as a leaf for the STF.
The leaf of this STF should be submitted with the append operation and would modify
the original STF for the study.
The leaf entries for the content files being provided in this submission should utilize the
replace operation as detailed in the eCTD Specifications.
The files that have been replaced in this submission will still be referenced by the preexisting STFs for the study but these files will no longer show as current because they
have been replaced in the backbone of the application.
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FDA Implementation of STF DTD v2.2


3. Deleting Files Cited by an Existing STF
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
Deleting from the STF Only
When a file is to be deleted from an STF but the file still needs to remain in the backbone
of the application (e.g., it is referenced by another STF), the index.xml for this
submission should contain a leaf entry with operation "delete" and the modified-file
attribute should include the index.xml#leafID for the instance to be deleted. No additional
STF file would be called for, since the file will be flagged as deleted in this instance.
Deleting from the Application Entirely
When a file is to be entirely deleted from the application (i.e., it is not referenced by any
other STF and is no longer needed as part of the application), no additional STF file is
called for. The lifecycle operation on the file to be deleted in the index.xml will flag the
file and any associated tags from the existing STFs as deleted. It is not necessary to
submit an accompanying STF when deleting a study report component file from the
application.
4. Correcting File-tag Values
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
When an applicant determines that an incorrect file-tag value has been assigned to a study
report component file in the STF, the applicant should "delete" the incorrectly tagged file
in the index.xml (to remove the file from any STF referencing it) and then reactivate the
file in the backbone by including a second leaf with the operation value "new". The file
does not need to be resubmitted; the reactivating xlink:href attribute points back to the
original location of the file.
Then, an STF referencing this new leaf entry should be submitted with the corrected file
tag value.
In the following example the applicant inadvertently tagged the synopsis file as a legacyclinical-study-report in submission serial 0000 and corrects the error in submission 0003.
In the serial 0000 index.xml,
<leaf checksum-type="MD5"
version=" " xlink:type="simple"

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FDA Implementation of STF DTD v2.2


checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="m4/42-stud-rep/423-tox/4231-single-dose-tox/synopsis-of-jm-12-345.pdf"
application-version="PDF 1.3"
ID="m42111">
<title>jm-12-345 Study Synopsis</title>
</leaf>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="m4/42-stud-rep/423-tox/4231-single-dose-tox/stf-jm-12-345.xml"
application-version="PDF 1.3"
ID="m42112">
<title>Study JM-12-345 STF</title>
</leaf>

In the serial 0000 stf-jm-12-345.xml file


<study-document>
<doc-content xlink:href = "../../../index.xml#m42111">
<file-tag name = "legacy-clinical-study-report" info-type = "ich"/>
</doc-content>
</study-document>

To correct the file-tag error, the following actions would be taken.


In the serial 0003 index.xml, delete the incorrect file-tag by deleting the file from the
index.xml which logically deletes the legacy-clinical-study-report file-tag associated with
it in the STF:
<leaf operation="delete"
checksum="" checksum-type="MD5"
modified-file="../0000/index.xml#m42111"
ID="idm4211stf">
<title/>
</leaf>

Then, add the file as "new" citing the location in the 0000 serial submission - there is no
need to send a second copy of the file:
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="../0000/m4/42-stud-rep/423-tox/4231-single-dose-tox/synopsis-of-jm-12345.pdf"
application-version="PDF 1.3"
<title>jm-12-345 Study Synopsis</title>
ID="r34567">
</leaf>

Page 15

FDA Implementation of STF DTD v2.2

Finally, include a new STF (using the "append" operation) and associate the correct
synopsis file-tag to the file.
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="append"
xlink:href="m4/42-stud-rep/423-tox/4231-single-dose-tox/stf-jm-12-345.xml"
modified-file="../0000/index.xml#m42112"
ID="r6789">
<title>Study JM-12-345 STF</title>
</leaf>

In the serial 0003 STF for JM-12-345, include the study-id tag to identify the study
report being modified and include the corrected file-tag metadata:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Single dose oral toxicity study in the mouse and dog</title>
<study-id>jm-12-345</study-id>
<category name="species" info-type="ich">mouse</category>
<category name="species" info-type="ich">dog</category>
<category name="route-of-admin" info-type="ich">oral</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../index.xml#r34567">
<file-tag name="synopsis" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>

VI. STUDY DATA MANAGEMENT OPTIONS


In most situations, one study would generate one STF and the information generated from
the study would reside together with the STF in the most appropriate subsection of the
CTD. However, there are certain situations where one study should generate more than
one STF representation. These situations might exist where:
different analyses with distinct life-cycle management needs co-exist and should
be distinguishable within the same section of the dossier
a study generates information that should be presented in a different subsection of
the CTD.

Page 16

FDA Implementation of STF DTD v2.2


A. Distinguishing Time -Specific Analyses Within the Same Subsection of the
CTD
In certain instances, the reporting of results can best be managed by maintenance
of more than one STF for the same study. This situation generally arises when
unique time point analyses (i.e. the latter analysis does not replace the earlier
analysis) have their own life-cycle management needs, and thus are better kept as
distinct reviewable units.
For example, in studies where patients continue to be followed and reported on
(with or without active dosing) beyond the official, protocol-defined, efficacy
and\or safety endpoints, the subsequent safety, efficacy or relapse analysis
supports a different clinical purpose than the earlier analysis and thus does not
replace or append the earlier analysis.
This can be illustrated through consideration of a study with protocol-defined
specific time point analyses (perhaps through a Drug Safety Monitoring Board)
that are required to be submitted and reviewed to continue the study. Thus, in one
submission, the Applicant provides safety and efficacy data for the subset of
patients with 12 weeks of exposure at that point in time. While this information is
being reviewed, the Applicant submits patient data from 18 weeks of exposure as
well as updates the 12-week database with the additional patients who have
achieved that length of exposure. In this instance, it would not be considered
appropriate to replace the 12-week data with the 18-week data. These two sets of
data should be kept as distinct, reviewable units of information with their own
lifecycle management needs.
B. Presenting Information from One Study in a Different Subsection of the
CTD
Some studies generate data supporting more than one section of the CTD. A
standard mechanism for placing this information in the appropriate CTD sections
should be available. For example, a safety and\or efficacy study might also have a
secondary purpose to perform a pharmacokinetic evaluation on all or some of
the patients in that study.
Filing all of this information (separate sets of analysis and supportive appendices
and datasets) under just one section of the dossier is considered unsatisfactory, as
there would be no method to associate the secondary information to the proper
section of the CTD. An approach might be to include the same all-inclusive
STF in both locations to alert the reviewers that there is information contained in
the STF applicable to more than one section of the CTD. However, this creates an
additional burden on the reviewer in identifying which datasets, listings and
appendices are relevant to the PK assessment and which are relevant to the full
safety\efficacy analysis.
Thus, an applicant should have the optional ability to organize these different sets
of information as discrete units by creating a second STF for the same study.
Page 17

FDA Implementation of STF DTD v2.2


Information that is shared by the two analyses (e.g., protocol, Case Report Form)
would be referenced by each STF while information that supports different
sections of the dossier could be clearly organized and submitted in the appropriate
CTD section. This is especially beneficial to applicants preparing two distinct
study reports for the study (one presenting the safety\efficacy analysis on all
patients and one presenting the pharmacokinetic analysis on the subset of patients
who participated in that part of the study).
VII. EXAMPLE SCENARIO
This section provides a series of sample submissions related to the same study and
illustrates how they would be accomplished using the Cumulative and Accumulative STF
approaches. Since FDA doe not use the Cumulative approach, the following instructions
are for the Accumulative approach.
Submission 0000
An applicant is providing information on a placebo-controlled study in the treatment of
nausea titled "Wonderdrug Study S107" performed under their in-house unique
identification "S107". In submission sequence number 0000, the applicant provides
interim study results in the form of an interim synopsis, the body of the interim study
report and the protocol for the study.
The index.xml for submission 0000 would contain four leaf entries; one for each content
file and one for the STF for the study as follows:
<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimedindication>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/synopsis.pdf"
application-version="PDF 1.3"
ID="a101">
<title>S107 Study Synopsis - Interim Results</title>
</leaf>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="new"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/study-report-body.pdf"
application-version="PDF 1.3"
ID="a102">
<title>S107 Study Report Body - Interim Results</title>
</leaf>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"

Page 18

FDA Implementation of STF DTD v2.2


checksum="98723f7594b5500a861509547c384e46" operation="new"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/protocol.pdf"
application-version="PDF 1.3"
ID="a103">
<title>S107 Study Protocol</title>
</leaf>
<leaf checksum-type="MD5"
version="STF Version 2.2" xlink:type="simple"
checksum="25d3b246313a9dbf688a48da2295260e" operation="new"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/stf-s107.xml"
ID="a104">
<title>Study Tagging File for S107</title>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimedindication>

The STF provided in submission 0000 is named "stf-s107.xml" and contains the
following information about the documentation being provided for study S107:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet-2-2.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Wonderdrug Study S107</title>
<study-id>S107</study-id>
<category name="type-of-control" info-type="ich">no-treatment</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#a101">
<file-tag name="synopsis" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#a102">
<file-tag name="study-report-body" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#a103">
<file-tag name="protocol-or-amendment info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.
Note: The type of control for this study was intentionally cited as no-treatment even
though the study is a placebo-controlled study. This will be corrected in a subsequent
submission (see submission 0002).

Page 19

FDA Implementation of STF DTD v2.2

Submission 0001
In a subsequent submission, the sponsor wishes to provide additional documentation on
Study S107. In submission 0001, the Sponsor provides the Sample Case Report Form and
a protocol amendment.
The index.xml for submission 0001 would contain three leaf entries; one for each content
file (i.e., the protocol amendment and the Sample CRD) and one for the STF. The leaf
entries for the new content files would be identical whether the Sponsor chooses to use
the Cumulative or Accumulative approaches. The leaf entry for the STF and the content
of the STF would differ depending on which approach was utilized.
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
The index.xml for submission 0001 would contain three leaf entries; one for each content
file (i.e., the protocol amendment and the Sample CRD) and one for the STF which
updates the previously submitted STF as shown here:
<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimedindication>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/protamend01.pdf"
application-version="PDF 1.3"
ID="a567">
<title>S107 Protocol Amendment No. 1</title>
</leaf>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="new"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/samplecrf.pdf"
application-version="PDF 1.3"
ID="a568">
<title>S107 Sample Case Report Form</title>
</leaf>
<leaf checksum-type="MD5"
version="STF Version 2.2" xlink:type="simple"
checksum="25d3b246313a9dbf688a48da2295260e" operation="append"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/stf-s107.xml"
modified-file="../0000/index.xml#a104"
ID="a569">

Page 20

FDA Implementation of STF DTD v2.2


<title>Study Tagging File for S107</title>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimedindication>

The new STF is also named "stf-s107.xml" and summarizes only the new information
being provided in this submission as follows:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-2-2stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Wonderdrug Study S107</title>
<study-id>S107</study-id>
<category name="type-of-control" info-type="ich">no-treatment</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#a567">
<file-tag name="protocol-or-amendment" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#a568">
<file-tag name="sample-case-report-form" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.

Submission 0002
In a subsequent submission, the sponsor wishes to provide additional documentation on
Study S107. In submission 0002, the Sponsor provides the final study report and synopsis
plus CRF files for two patients who died during the conduct of the study. In addition, it
was finally noticed that the previous STFs had incorrectly identified the study as an
uncontrolled study when, in fact, it was placebo-controlled.
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
The index.xml for submission 0002 would contain five leaf entries; one for each content
file (i.e., synopsis, study report and two patient CRF files) and one for the STF which
would append the previously submitted STF as shown here:
Page 21

FDA Implementation of STF DTD v2.2


<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimedindication>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="replace"
xlink:href="m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/synopsis.pdf"
modified-file="../0000/index.xml#a101"
application-version="PDF 1.3"
ID="r345">
<title>S107 Study Synopsis - Final</title>
</leaf>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="replace"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/s107body.pdf"
modified-file="../0000/index.xml#a102"
application-version="PDF 1.3"
ID="r346">
<title>S107 Study Report - Final</title>
</leaf>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/crf/11/12.pdf"
application-version="PDF 1.3"
ID="r347">
<title>CRF for Subject S107-11-12</title>
</leaf>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="new"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/crf/162/5045.pdf"
application-version="PDF 1.3"
ID="r348">
<title>CRF for Patient S107-162-5045</title>
</leaf>
<leaf checksum-type="MD5"
version="STF Version 2.2" xlink:type="simple"
checksum="25d3b246313a9dbf688a48da2295260e" operation="append"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/stf-s107.xml"
modified-file="../0001/index.xml#a569"
ID="r349">
<title>Study Tagging File for S107</title>
</leaf>

Page 22

FDA Implementation of STF DTD v2.2


</m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimedindication>

The new STF is named "stf-s107.xml" and identifies the additional documentation
provided for Study S107 in this submission. The information in this STF also corrects the
erroneous type-of-control category tag to placebo as follows:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet-2-2.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Wonderdrug Study S107</title>
<study-id>S107</study-id>
<category name="type-of-control" info-type="ich">placebo</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#r345">
<file-tag name="synopsis" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r346">
<file-tag name="study-report-body" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r347" >
<property name="site-identifier" info-type="us">11</property>
<file-tag name="case-report-forms" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r348" >
<property name="site-identifier" info-type="us">162</property>
<file-tag name="case-report-forms" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.

Page 23

SECTION 11

eCTD Change Control Process v1.8

This document establishes the change control process for the eCTD Specification.
Change control for regional eCTD Module 1 specifications is the regional
authority's responsibility.

ICH eCTD Specification Change Control V1.8


Document Change History
Date

Version
Number
Version 1.0
Version 1.1

December 2002

Version 1.2
Version 1.3

January 2003
January 2003

Version 1.4
Version 1.5
Version 1.6
Version 1.7

February 2003
July 15, 2003
July 17, 2003
July 18, 2003

Version 1.8

June 10, 2004

Description
Initial Baseline
Teleconference review of required
section
Revised by subsection of M2 EWG
Comments from subset of M2
members
ICH Tokyo M2 Meeting
ICH Brussels M2 Meeting
ICH Brussels M2 Meeting
ICH Brussels M2 Meeting FDA
Lawyer Comments
ICH Tysons Corner Meeting Add
release schedules

ICH eCTD Specification Change Control V1.8


Contents
Introduction......................................................................................................................... 1
Scope ............................................................................................................................... 1
Purpose ............................................................................................................................ 1
Members .......................................................................................................................... 1
Change Control Process...................................................................................................... 2
Change Requests.............................................................................................................. 2
eCTD Change Control Meetings ..................................................................................... 3
Emergency Meetings ....................................................................................................... 3
Preparing for the Meeting................................................................................................ 3
Change Control Review................................................................................................... 3
Approved Change Requests............................................................................................. 4
eCTD Release Schedule...................................................................................................... 1
Major Releases ................................................................................................................ 1
Release Planning .........................................................
Minor Releases ................................................................................................................ 1

ICH eCTD Specification Change Control V1.8

Introduction
At the September 2002 ICH Steering Committee meeting, the ICH M2 Expert Working
Group (EWG) presented the signed Step 3 eCTD Specification for Step 4 consideration
by the ICH Steering Committee. The Steering Committee signed the specification to Step
4 and tasked the M2 EWG to also be the Implementation Working Group (IWG) for the
eCTD Specification. To implement the eCTD across all three regions, change control
should be in place to effectively communicate and execute changes to the eCTD
Specification.
Scope
This document establishes the change control process for the eCTD Specification.
Change control for regional eCTD Module 1 specifications is the regional authoritys
responsibility.
Purpose
The eCTD IWG is authorised by the ICH Steering Committee to administer changes to
the eCTD Specification. Change control is established to serve the following purposes:
Evaluate and approve or disapprove proposed changes to the eCTD Specification
Ensure implementation of approved changes
Represent the interests of all groups who might be affected by changes
Members
The eCTD IWG consists of a Topic Leader, Deputy Topic Leader, and Experts from each
of the six ICH parties, and ICH observers. The Steering Committee can also nominate, or
the eCTD IWG can request, additional members to work with the eCTD IWG to support
eCTD change control.
These members of the eCTD IWG are responsible for performing functions related to
eCTD change control.
Rapporteur
The eCTD IWG Rapporteur will be responsible for:
Organising and presenting change requests to eCTD IWG in RTF format
Presenting results of eCTD change control meetings to ICH Steering Committee
Ensuring results of change control meetings are posted on the ICH Web site
(www.ich.org)
Identifying change requests in the eCTD Q&A document
Topic Leaders/Deputy Topic Leaders
The Topic Leaders for ICH parties will be responsible for:
Submitting their partys vote on eCTD change control
Assigning regional members to present change requests originating in their region as
needed

ICH eCTD Specification Change Control V1.8


Experts
Experts from each region will be responsible for:
Defining issues related to change requests
Providing practical solutions
Secretary
The eCTD IWG Secretary will be responsible for:
Recording approved change requests
Recording change control meeting minutes

Change Control Process


Change Requests
Change requests can originate in ICH CTD change control or through eCTD
implementation, as follows:
1. During CTD change control process, CTD IWGs should consult with the eCTD IWG.
All change requests from a CTD IWG should be documented, showing concurrence
of all ICH parties, including the eCTD IWG, and should receive Steering Committee
approval prior to being submitted to the eCTD IWG as a change request. The eCTD
IWG Rapporteur should make CTD changes a high priority on the eCTD change
control list.
2. For change requests originating in an ICH region, the change request could be
submitted by any interested party to an eCTD IWG member from their region.
Change requests from non-ICH regions can be forwarded to the eCTD IWG
Rapporteur or the ICH Secretariat. Prior to being submitted to the eCTD IWG, the
proposed change should undergo any necessary testing by the eCTD IWG parties in
the region sponsoring the request. Change requests should then be forwarded to the
eCTD IWG Rapporteur for tracking, submission, and resolution.
A change request form is provided in Appendix A. The form is for change requests
originating outside of ICH.

ICH eCTD Specification Change Control V1.8


Each change request should contain at least the following information:
Contact information
Summary of the problem, including rationale
Reference to the area of the specification to be changed
Version number and date of the eCTD specification
Detailed description, including results of any testing
Recommended solution, if any
eCTD Change Control Meetings
One day will be set aside at each M2 EWG meeting for eCTD change control. Meetings
can take place at regularly scheduled ICH Steering Committee meetings or via meetings,
teleconferences, or videoconferences approved by the Steering Committee.
Emergency Meetings
Any member of the eCTD IWG can request that the Rapporteur schedule an emergency
eCTD change control meeting.
Preparing for the Meeting
A list of change requests will be organised and presented by the Rapporteur to the eCTD
IWG prior to each change control meeting.
Change Control Review
Change requests would be categorised by the Rapporteur prior to the eCTD change
control meeting.

Any change requests requiring testing will be assigned to a sub group of the eCTD
IWG
Change requests not requiring additional testing will be sent to the eCTD IWG prior
to the next change control meeting
A discussion of the disposition of a change request with input from each ICH party
will occur at the change control meetings. Any requests that required testing will be
presented by the sub group assigned to the testing. This discussion can involve CTD
review if additional information on the initial change request and/or proposed
solution is warranted.

After the discussion, the change request would take one of the following paths:
1. Defined as out the of scope of eCTD IWG include:

Is not relevant
Involves a significant new concept
Involves the M2 EWG or other ICH groups and the ICH step process to make the
necessary eCTD change
3

ICH eCTD Specification Change Control V1.8

2. Defined as in the scope of the eCTD IWG: can be processed by the eCTD IWG and
would take one of the following paths:
Approved by a unanimous vote from all six ICH parties
Specification change
Q&A document
Deferred to
Next change control meeting
Assigned to a subgroup for testing
Rejected
Additional testing may be called for before a change request can be fully evaluated.
When a change request is assigned for testing, a particular ICH party, or members from
each party, can be assigned to test the change request. The change request would stay on
the eCTD change control agenda and be presented at the next change control meeting for
additional review.
Approved Change Requests
Change requests approved by the eCTD IWG would either be addressed in Q&A or
implemented into the eCTD specification by the Rapporteur and presented to the ICH
Steering Committee for approval.
The recommendation on which versions of the eCTD specification will be supported by
regulators will be provided with each new eCTD version.
Documentation
Once approved by the Steering Committee, the following documentation would be
posted on the ICH Web site:
New Version of the eCTD Specification
Updated change request tracking document that includes the status of approved,
rejected, and deferred requests
Appendix B displays the process flow of an eCTD change request.

ICH eCTD Specification Change Control V1.8

eCTD Release Strategy


Stability of the ICH eCTD Specification is important to ensure that industry and
regulators can develop or procure efficient tools. In order to provide this stability, the
ICH eCTD Specification will follow a specific release strategy that allows software
application developers and managers to plan for the future.
Major Releases
Major new releases of the eCTD Specification will be announced at least two years
before Step 4. Major releases include changes that significantly impact the DTD,
completely modify the eCTD architecture, or significantly impact the software
applications being used in the three regions. These major releases will be addressed by
the M2 Expert Working Group (EWG) and follow the ICH step process. Following this
process allows comments from parties external to ICH.
Major releases will be identified by a new numbering sequence (e.g., 4.0).
Minor Releases
In between major releases of the ICH eCTD Specification, the eCTD Implementation
Working Group (IWG) could also release new, minor releases of the ICH eCTD
Specification. The scope of these minor releases will be to correct minor issues with the
specification that hinder eCTD implementation or software application development.
Since these are minor modifications to the eCTD Specification, notification will occur
when the minor release is published on the ICH Web site.
Minor releases will continue the numbering sequence of the last major release (e.g., 4.1).
Version Compatibility
Backwards compatibility will be considered for each eCTD Specification release.
Descriptions of the scope of each change will be provided with each new release.

SECTION 12

eCTD Change Request Form

This form should be used to request a change to the ICH eCTD Specification.
The change can be to fix a perceived bug, meet a new requirement or to
enhance existing functionality.

ICH eCTD Specification Change Control V1.8

INTERNATIONAL CONFERENCE ON HARMONISATION OF


TECHNICAL REQUIREMENTS FOR REGISTRATION OF
PHARMACEUTICALS FOR HUMAN USE

Change Control Process for the eCTD


Version 1.8
June 10, 2004

APPENDIX A: ECTD Q&A OR CHANGE REQUEST


This form should be used to request a change to the ICH eCTD Specification. The
change can be to fix a perceived bug, meet a new requirement or to enhance existing
functionality. Please provide the following information.

Contact Information
Organisation Name:
Organisation
Address:
Contact Name:
Address:
Telephone Number:
E-mail Address:

Question or Change Request


Summary

Submit Date
Item to be
Changed/ Question
Version Number
and Date
Description

This should be a short summary of the problem submitted including


rationale.
Date you submit the change request (YYYY-MM-DD)
Reference to the area of the specification to be changed (e.g., the eCTD
DTD, the written specification, the M2 eCTD style sheet)
Indicate the specific version and date of the eCTD Specification for
which the change is proposed.
Provide a detailed explanation of the problem, any known solutions, and
steps on how to recreate the error, if applicable. If this is a new
requirement or enhancement, please provide the reason for the
requirement or enhancement and any known solutions. If you have any
sample output, sample code or other examples to help clarify the
description, attach the samples to this form. You should also provide a
detailed description of any testing or research that was done to support
the solution(s) being proposed and any advice on backward compatibility
issues.

Submit a completed copy of this form to an eCTD IWG member in your region in RTF
format. Those not residing in an ICH region can forward this request to the eCTD IWG
Rapporteur or to the ICH Secretariat at the following address. An electronic copy is
preferred with the subject field eCTD Change Request.
ICH Secretariat
c/o IFPMA,
30 rue de St-Jean
P.O. Box 758
1211 Geneva 13, Switzerland
Tel: +41 (22) 338 32 06, Telefax: +41 (22) 338 32 30
E-mail : ich@ifpma.org

SECTION 13

eCTD Specification v 3.2

This document describes the parts of the registration application that are common
to all regions and some of the lifecycle requirements for products. The parts of
the registration application that are specific to a region will be covered by regional
guidance. However, this backbone has been developed to handle both the regional
and common parts of submissions.

ICH eCTD Specification V 3.2 February 04, 2004

INTERNATIONAL CONFERENCE ON HARMONISATION OF


TECHNICAL REQUIREMENTS FOR REGISTRATION OF
PHARMACEUTICALS FOR HUMAN USE

ICH M2 EWG
Electronic Common Technical Document Specification

This specification has been developed by the ICH M2 Expert Working


Group and maintained by the eCTD Implementation Working Group in
accordance with the ICH Process as pertains to the M2 EWG and eCTD
change control as it pertains to the eCTD IWG.

ICH eCTD Specification V 3.2 February 04, 2004

Document Change History


Version
Number

Date

Version 3.0
Version 3.1

October 2003
November 2003

Version 3.2

February 2004

Description

Initial Step 4 Document


Incorporate approved change requests
00020, 00030, 00090, 00110, 00190,
00200, 00240, 00260, 00290, 00310,
00380, 00400, 00420, 00450, 00480,
00500, 00510, 00520, 00530
Editorial Corrections and Change to
Align with the M4 Organisation
Document : Granularity Annex

ICH eCTD Specification V 3.2 February 04, 2004

ICH eCTD Specification ................................................................................................................................ 1


Introduction ................................................................................................................................................ 1
Background ................................................................................................................................................ 1
Scope .......................................................................................................................................................... 1
Requirements.............................................................................................................................................. 1
Change Control........................................................................................................................................... 2
Appendix 1: Overall Architecture ............................................................................................................... 1-1
Guiding Design Principles....................................................................................................................... 1-1
Business Model ....................................................................................................................................... 1-1
Modular Structure of the eCTD............................................................................................................... 1-1
XML Based eCTD................................................................................................................................... 1-1
Multiple Region Support ......................................................................................................................... 1-2
Lifecycle Management ............................................................................................................................ 1-2
Appendix 2: The eCTD Submission............................................................................................................ 2-1
Introduction ............................................................................................................................................. 2-1
The eCTD Submission ............................................................................................................................ 2-1
Directory Structure .............................................................................................................................. 2-1
XML eCTD Instance ........................................................................................................................... 2-1
eCTD Template ....................................................................................................................................... 2-1
Logical Documents and Files .................................................................................................................. 2-1
Formats.................................................................................................................................................... 2-2
Common Formats .................................................................................................................................... 2-2
Regional Use of Other Formats ............................................................................................................... 2-2
Links........................................................................................................................................................ 2-2
Presentation ............................................................................................................................................. 2-2
Checksums............................................................................................................................................... 2-3
Element to File Directory Mapping......................................................................................................... 2-3
File Extension.......................................................................................................................................... 2-4
Name ....................................................................................................................................................... 2-4
References ............................................................................................................................................... 2-5
Appendix 3: General Considerations for the CTD Modules ....................................................................... 3-1
Introduction ............................................................................................................................................. 3-1
Folder and File Naming Conventions...................................................................................................... 3-1
Screenshots and Folder Hierarchy........................................................................................................... 3-1
Module 1 Administrative Information and Prescribing Information ....................................................... 3-2
Module 2 Summaries............................................................................................................................... 3-2
Module 3 Quality..................................................................................................................................... 3-2
Module 4 Nonclinical Study Reports ...................................................................................................... 3-5
Module 5 Clinical Study Reports ............................................................................................................ 3-8
Appendix 4: File Organization for the eCTD .............................................................................................. 4-1
Appendix 5: Region Specific Information Including Transmission and Receipt ........................................ 5-1
Introduction ............................................................................................................................................. 5-1
Region Specific Information: Module 1 .................................................................................................. 5-1
Region ................................................................................................................................................. 5-1
Submission Addresses ............................................................................................................................. 5-1
Media....................................................................................................................................................... 5-2
Cover Letter............................................................................................................................................. 5-2
Preparing the Media ................................................................................................................................ 5-2
Transport ................................................................................................................................................. 5-2
Security.................................................................................................................................................... 5-2
Receipt..................................................................................................................................................... 5-3
Acknowledgment..................................................................................................................................... 5-3
Appendix 6: The eCTD XML Submission.................................................................................................. 6-1
Background ............................................................................................................................................. 6-1
File Names and Directory Structure ........................................................................................................ 6-1
Lifecycle Management ............................................................................................................................ 6-2

ICH eCTD Specification V 3.2 February 04, 2004

Operation Attribute.................................................................................................................................. 6-3


DTD Content Model................................................................................................................................ 6-5
eCTD Element/Attribute Instructions...................................................................................................... 6-7
Instructions for a Simple New Submission ............................................................................................. 6-9
Instructions for an Amendment, Supplement, or Variation................................................................... 6-10
Instructions for Multiple Indications ..................................................................................................... 6-10
Instructions for Multiple Drug Substances, Manufacturers, and Products ............................................ 6-11
Instructions for Extending XML eCTD DTD Elements........................................................................ 6-13
Instructions for Submitting Sections as Paper ....................................................................................... 6-13
Appendix 7: Specification for Submission Formats .................................................................................... 7-1
Introduction ............................................................................................................................................. 7-1
PDF.......................................................................................................................................................... 7-1
Version ................................................................................................................................................ 7-1
Fonts .................................................................................................................................................... 7-1
Definition of Subset............................................................................................................................. 7-1
Notes on Embedding Japanese Fonts: ................................................................................................. 7-1
Font Size.............................................................................................................................................. 7-2
Use of Color Fonts............................................................................................................................... 7-2
Page Orientation .................................................................................................................................. 7-2
Page Size and Margins ........................................................................................................................ 7-2
Source of Electronic Document........................................................................................................... 7-2
Methods for Creating PDF Documents and Images ............................................................................ 7-3
Hypertext Linking and Bookmarks ..................................................................................................... 7-3
Page Numbering .................................................................................................................................. 7-4
Document Information Fields.............................................................................................................. 7-4
Open Dialog Box................................................................................................................................. 7-4
Security................................................................................................................................................ 7-4
Indexing PDF Documents ................................................................................................................... 7-4
Use of Acrobat Plug-Ins ...................................................................................................................... 7-4
XML Files ............................................................................................................................................... 7-4
SVG Files ................................................................................................................................................ 7-5
Appendix 8: XML eCTD DTD ................................................................................................................... 8-1
Appendix 9: Glossary .................................................................................................................................. 9-1

ICH eCTD Specification V 3.2 February 04, 2004

ICH eCTD Specification


Introduction
The ICH M4 Expert Working Group (EWG) has defined the Common Technical Document (CTD). The
ICH M2 EWG has defined, in the current document, the specification for the Electronic Common
Technical Document (eCTD). The eCTD is defined as an interface for industry to agency transfer of
regulatory information while at the same time taking into consideration the facilitation of the creation,
review, lifecycle management and archival of the electronic submission. The eCTD specification lists the
criteria that will make an electronic submission technically valid. The focus of the specification is to
provide the ability to transfer the registration application electronically from industry to a regulatory
authority. Industry to industry and agency to agency transfer is not addressed.
The specification is divided into a series of main sections followed by a number of appendices in which
detailed technical specifications are given

Background
The specification for the eCTD is based upon content defined within the CTD issued by the ICH M4 EWG.
The CTD describes the organization of modules, sections and documents. The structure and level of detail
specified in the CTD have been used as the basis for defining the eCTD structure and content but where
appropriate, additional details have been developed within the eCTD specification.
The philosophy of the eCTD is to use open standards. Open standards, including proprietary standards,
which through their widespread use can be considered de facto standards, are deemed to be appropriate in
general.

Scope
The CTD as defined by the M4 EWG does not cover the full submission that is to be made in a region. It
describes only modules 2 to 5, which are common across all regions. The CTD does not describe the
content of module 1, the Regional Administrative Information and Prescribing Information, nor does it
describe documents that can be submitted as amendments or variations to the initial application.
The value of producing a specification for the creation of an electronic submission based only upon the
modules described in the CTD would be limited. Therefore, the M2 EWG has produced a specification for
the eCTD that is applicable to all modules of initial registration applications and for other submissions of
information throughout the lifecycle of the product, such as variations and amendments.
This document describes the parts of the registration application that are common to all regions and some
of the lifecycle requirements for products. The parts of the registration application that are specific to a
region will be covered by regional guidance. However, this backbone has been developed to handle both
the regional and common parts of submissions.

Requirements
The specification is designed to support high-level functional requirements such as the following:

Page 1

Copy and paste


Viewing and printing of documents
Annotation of documentation
Facilitate the exporting of information to databases
Searching within and across applications
Navigation throughout the eCTD and its subsequent amendments/variations

ICH eCTD Specification V 3.2 February 04, 2004

Change Control
The specification for the eCTD is likely to change with time. Factors that could affect the content of the
specification include, but are not limited to:
Change in the content of the CTD, either through the amendment of information, at the same level
of detail, or by provision of more detailed definition of content and structure
Change to the regional requirements for applications that are outside the scope of the CTD
Updating standards that are already in use within the eCTD
Identification of new standards that provide additional value for the creation and/or usage of the
eCTD
Identification of new functional requirements
Experience of use of the eCTD by all parties
Details of the change control management are described in an external ICH document.

Page 2

Appendix 1: Overall Architecture


Guiding Design Principles
This appendix defines the basic principles that drove the design and architecture of the eCTD. Detailed
specifications are defined in appendices 2 and 6.

Business Model
The business process to be supported can be described as follow:
Industry <-----> Message <------> Agency
The business process defines specific requirements for the message.
The primary focus of the eCTD is to provide a data interchange message between industry and agencies.
Industry initiates the process by creating the initial submission in terms of an electronic CTD. Throughout
the lifecycle of this process, additional information will be submitted to update or modify the information
contained in the initial submission (e.g., supplement, amendment, variation.) The agency can submit
acknowledgements, queries and requests to industry. These are considered simple messages using
electronic mail or other transport formats. The overall architecture of the eCTD is designed to provide a
commonly agreed upon submission and submission structure that imposes minimal restriction to the
industry and agencies.

Modular Structure of the eCTD


The structure of the electronic submission in terms of organization and navigation should be consistent with
the modular structure of the Common Technical Document. The goal of this design principle is to
standardize the electronic format of the common parts of the eCTD.

XML Based eCTD


The XML eCTD DTD (Document Type Definition) defines the overall structure of the submission. The
purpose of the XML backbone is two-fold: (1) to manage meta-data for the entire submission and each
document within the submission and (2) to constitute a comprehensive table of contents and provide
corresponding navigation aids. Meta-data on submission level include information about submitting and
receiving organization, manufacturer, publisher, ID and kind of the submission, and related data items.
Examples for meta-data on document level are versioning information, language, descriptive information
such as document names and checksums. Details are defined in appendix 6.
The XML instance of any submission should be created and validated according to the XML eCTD DTD as
defined in appendix 8.
The XML eCTD DTD describes the hierarchical structure according to the CTD as defined by the ICH M4
Expert Working Group. It includes multiple hierarchical levels depending on the specific module as
defined in the CTD. The actual submission can include more hierarchical levels below those defined in the
CTD. The XML eCTD instance covers the entire submission including all hierarchical levels and includes
references to each individual file.
The submission should include a Stylesheet that supports presentation of the XML instance, navigation
according to the table of contents, and provides access to all documents within the submission. A standard
Stylesheet for viewing the eCTD submission is defined and provided by the ICH M2 EWG. Presentation
and navigation via other Stylesheets on the receiving side should be possible.
The XML eCTD DTD includes a reference for each document to the physical file within the folder
structure. The XML eCTD DTD includes attributes for descriptive names of folders and documents.

Page 1-1

Multiple Region Support


The scope of each submission is global according to the Common Technical Document, meaning that
modules 2 through 5 of a submission are intended for all regions with the exception of selected documents
(e.g., in the quality module), which have a regional scope. Module 1 of a submission is regional in nature.
The DTD as defined by the ICH M2 expert working group specifies the structure of the common parts of
the eCTD primarily focusing on module 2 through 5. It allows linking to regional DTDs for module 1,
which will be defined by the authorities in each region.

Lifecycle Management
The applicant creates a submission that is stored in a local repository. The applicant submits the initial
submission to the agency, which imports the submission into another local repository. The nature and kind
of the local repositories is not within the scope of the eCTD. The initial submission should be selfcontained meaning that it includes all documents and no references to other submissions. Regional
guidance should be consulted if references to other submissions are needed.
Following the initial submission, the applicant can submit incremental updates such as amendments and
variations. Updates can refer to documents in the previous submissions. Updates should be designed in a
way that they can be loaded into the repository by fully preserving the initial or previous submission via
version control. The XML backbone should include meta-data identifying the update and providing
navigation aids to filter for different submission types.
It is preferred that when a Common Technical Document is submitted electronically, the entire submission
should be in electronic form with the exception of certain regional forms that currently require written
signatures. See appendix 5 for regional requirements. See appendix 6 for a description of how to submit a
CTD containing both paper and electronic components.

Page 1-2

Appendix 2: The eCTD Submission


Introduction
This appendix specifies the Information Technology aspect of the eCTD submission. Informally, the eCTD
submission is a directory structure with files including the XML eCTD instance, reports, data and other
submission information. The eCTD submission supports multilingual and multi-region aspects.

The eCTD Submission


An eCTD submission is a collection of data objects that follows the eCTD specification. The main function
of the eCTD submission is data exchange. Information systems would have to be created to process the
eCTD submission. The biggest benefits are expected when the eCTD submission is loaded into an
information system that supports the review process. However, one can view an eCTD submission with a
Web browser as it is Web ready. In the Web environment, the eCTD submission should be usable without
processing in at least in the following ways:
Standalone: Viewable with a Web browser.
Network: Loadable into a Web server.
The eCTD submission is composed of the following:
Directory structure
XML eCTD instance
Content files

Directory Structure
The directory structure is a structure of directories and files. There should be a reasonable maximum
number of entries (directories and files) per directory. The directory structure should follow the rules
below. The files could be in several formats as specified of below.
The name of the files and directories are identifiers. They should be short. The file names are not intended
to convey meta-data, though some meaning in the names helps (i.e., no random names.)
Highly recommended names for directories and files are provided in Appendix 4. Any directory names and
file names that are added to the eCTD submission by the applicant should be descriptive and logical.

XML eCTD Instance


The instance is in the submission sequence number directory (see appendix 6). The submission sequence
number directory should contain at least two files and one or more directories. One of the files in the
submission sequence directory is the instance and the other is the MD5 checksum of the instance. The
instance is the starting file for the processing by an XML processor.
The intention is to have links from the instance to leaf files in the eCTD submission as opposed to creating
a single XML document that contains the entire eCTD submission. The instance should contain mostly
linking facilities to the leaf files. The instance also contains meta-data at the leaf level.

eCTD Template
The ICH Web site includes an eCTD template that is an empty directory. It is an illustration of an eCTD
submission and it is ready to be populated with the applicant data. Appendix 4 defines the directories used
to create this template.

Logical Documents and Files


A logical document comprises one or more CTD table of contents sections that together contain the
minimum amount of information to be exchanged. In general, the XML eCTD DTD should map explicitly
to the CTD table of contents, but there are exceptions where the XML eCTD DTD may map to the level of

Page 2-1

use designated by the appropriate ICH CTD Implementation Working Group (IWG) instead. Ideally, a
logical document consists of a single physical file. In the event the physical file exceeds the recommended
maximum file size due to graphics, data content, scanned images, or other large format content, additional
files can make up the logical document. Furthermore, if the logical document consists of multiple file
formats, then more than one physical file would be needed. An example of such a case would be PDF and
XML data that together represent the logical document.

Formats
Formats should be readable at least for as long as it is needed for the regulatory process. This process could
be very long; (e.g., 50 years.) This points to neutral formats: formal standard, industrial standard, vendor
independent, and text-like. The format should be adapted to the type of data. Appendix 7 describes the
way in which these files should be constructed.
The list of agreed to formats will be updated as technology evolves and new requirements arise. XML will
be the preferred format for all types of data.

Common Formats
The common formats that can be included in an eCTD submission are:
Narrative: Portable Document Format (PDF)
Structured: Extensible Markup Language (XML)
Graphic: Whenever possible, use PDF. When appropriate or when PDF is not possible, use Joint
Photographic Experts Group (JPEG), Portable Network Graphics (PNG), Scalable Vector Graphics
(SVG), and Graphics Interchange Format (GIF). Special formats for very high resolutions may be
appropriate on a case-by-case basis.

Regional Use of Other Formats


Regulatory authorities and applicants could agree to use other formats regionally (i.e., non-common
formats or uses of the common formats in a different way from above.) The use of other formats is
discouraged and the intention is to use as much as possible the common formats. The intention of the use of
other formats is for transition.
There are two classes of transitions:
Legacy Transition: from the past to the present (i.e., old formats to present formats.)
Future Transition: from the present to the future (i.e., from present formats to new formats.) The new
formats would normally be candidates for common formats.

Links
Links among objects in the eCTD submission should be relative. The intention is to make the eCTD
submission self-contained. All literature references introduced by the applicant should be included in the
submission.
One can always point to a file. The capacity to point to a specific location within a file depends on the
linking technology. Different formats allow for the use of different linking technology. See Appendix 7.

Presentation
Presentation is closely associated with formats. To associate a Stylesheet with a file usually one has to use a
linking technology. The linking between Stylesheet (that could be in a separate file) and a data file should
be relative. In addition, there is the dimension of media. One file could have several Stylesheets; the one
used depends on the media. For example, there could be one presentation for the screen and another for
paper.

Page 2-2

Checksums
The eCTD submission should contain checksums for each individual file including a checksum file for the
eCTD XML instance. Initially, the MD5 Message-Digest Algorithm (MD5) should be used for this
purpose. Including a checksum for each individual file provides a number of benefits including:
The integrity of each file can be verified by comparing the checksum submitted with the file and
the computed checksum.
The checksum can be used to verify that the file has not been altered in the historical archive of
the regulatory authority. This is especially useful as the files are migrated from one storage
medium to another, as in the case of backup to magnetic tape storage.

Element to File Directory Mapping


Follow these rules:
The rules below for the file and directories take precedence.
Add the corresponding extension to the file.
If needed, use a reasonable abbreviation.

Page 2-3

File Extension
All files should have one and only one file extension. The file extension should be used to indicate the
format of the file. For example:
hello.pdf
hello.rtf

PDF
RTF

The mapping between formats and extensions are:


IANA nomenclature
text/css
text/html
text/xml
application/pdf
application/rtf
application/vnd.ms-excel
image/jpeg
image/png
image/gif

css
html or htm
xml
pdf
rtf
xls
jpg
png
gif

Non IANA nomenclature


DTD
XPT (SAS)
XSL

dtd
xpt
xsl

The eCTD submission could use formats not registered with the Internet Assigned Numbers Authority
(IANA).
The presence of a format in this list does not imply that it would be considered an acceptable format. For
formats absent from this list, widely used mapping between the formats and the extensions should be used.
Future direction: if a mechanism (e.g., standard) becomes available that associates the formats with file
extension; it should be considered for this specification.

Name
Name is a token composed of the following characters:
Letters "a" to "z" [U+0061 to U+007A].
Digits "0" to "9" [U+0030 to U+0039].
"-" [HYPHEN-MINUS, U+002D].
The notation "U+" refers to the Unicode [UNICODE] notation.

Page 2-4

Correct names (only the name without the extension):


part-b
myfile
hello
Incorrect names (only the name without the extension):
part a
(' ' ; SPACE is not allowed)
myfile.xml
('.' ; FULL STOP is not allowed)
hello:pdf
(':' ; COLON is not allowed)
part_a
(_, LOW LINE is not allowed)
Parta
(UPPERCASE is not allowed)
Directory name is a name.
File name is one name followed by one name separated by a
'.' (FULL STOP, U+002E).
Correct file names (with the extension):
myfile.pdf
hello.cml
Incorrect file names (with the extension)::
a part.pdf (' '; SPACE is not allowed)
hello
(missing extension)
hello:xml
(':'; COLON is not allowed)
The maximum length of the name of a single folder or file is 64 characters including the extension. Only
lower case letters should be used in all file and directory names. The maximum length of a path is 230
characters, including file name, and extension. This allows regulators 26 characters to add to the path in
their review environments. If the path exceeds the 230 character limit, then folder and file names created
by the applicant, and not those listed in Appendix 4 should be abbreviated first. Applicants should also
consult regional media formats and M2 EWG recommendations for possible folder limits imposed by the
media.
Document name is the first name in the file name. For example, docname in the file name
docname.ext.

Character encoding
The character encoding (charset) in order of preference is:
Unicode UTF-8, Unicode 16 bits [ISO-10646].
ISO-8859-1 (Latin-1) or appropriate ISO-8859-x; e.g., ISO-8859-7 for Greek.
The appropriate SHIFT_JIS.
Other character encoding agreed upon regionally by the regulatory authority and applicant.

References
[CML] Chemical Markup Language
http://www.xml-cml.org
[CSS2] Cascading Style Sheets, level 2
http://www.w3.org/TR/REC-CSS2
[ECMAScript] ECMAScript Language Specification, 3rd edition. ECMA- 262
http://www.ecma.ch/ecma1/STAND/ECMA-262.HTM

Page 2-5

[EXCEL] Microsoft Excel


http://www.microsoft.com/office/excel/default.htm
[GIF] Graphics Interchange Format
http://tronche.com/computer-graphics/gif/gif89a.html
[HTML] HTML 4.01 Specification
http://www.w3.org/TR/html4
[IANA] Internet Assigned Numbers Authority
http://www.iana.org
[IMT] Internet Media Types
http://www.isi.edu/in-notes/iana/assignments/media-types/media-types
[ISO-10646] Information Technology -- Universal Multiple-Octet Coded
Character Set (UCS) -- Part 1: Architecture and Basic Multilingual
Plane, ISO/IEC 10646-1:1993
[ISO-639] Codes for the representation of names of languages
ISO 639:1988.
http://www.iso.ch/cate/d4766.html
http://www.oasis-open.org/cover/iso639a.html.
[JPEG] Joint Photographic Experts Group
http://www.jpeg.org/public/wg1n1807.txt
[MD5] The MD5 Message-Digest Algorithm
http://ietf.org/rfc/rfc1321.txt
[PDF] Portable Document Format
http://partners.adobe.com/asn/developer/technotes.html#pdfspec
[PNG] PNG (Portable Network Graphics) Specification Version 1.0
http://www.w3.org/TR/REC-png.html
[RTF] Rich Text Format (RTF) Specification, version 1.6
http://msdn.microsoft.com/library/specs/rtfspec.htm
[SVG] Scalable Vector Graphics (SVG) 1.0 Specification (work in progress)
http://www.w3.org/TR/1999/WD-SVG-19991203
[UNICODE] Unicode Consortium
http://www.unicode.org
[XHTML] XHTML 1.0: The Extensible HyperText Markup Language
http://www.w3.org/TR/WD-html-in-xml
[XML] Extensible Markup Language (XML) 1.0 (Second Edition)
http://www.w3.org/TR/REC-xml.html
[XSL] Extensible Stylesheet Language (XSL)
W3C Candidate Recommendation 21 November 2000 (work in progress)
http://www.w3.org/TR/WD-xsl

Page 2-6

Appendix 3: General Considerations for the CTD Modules


Introduction
Documents that are provided in the different modules should be formatted as defined by the ICH Common
Technical Document. There should also be consistency in the way navigational aids are provided. Within
each document, bookmarks and hypertext links from the table of contents should be provided to all tables,
figures, publications, and appendices.
Hypertext links should be provided throughout the body of these documents to aid efficient navigation to
annotations, related sections, publications, appendices, tables, and figures that are not located on the same
page. If a list of references is included at the end of a document, there should be hypertext links to the
appropriate publication.
Documents should be generated from electronic source documents and not from scanned material, except
where access to the source electronic file is unavailable or where a signature is required.

Folder and File Naming Conventions


Highly recommended folder and file names are presented in this specification. This could be used in most
cases, however applicants may modify this specification where appropriate.1 For example, include an
additional folder for information where an appropriate folder name is unavailable in the eCTD
specification. It is recommended that applicants maintain folder names listed in this specification. This
should not be interpreted to mean that the actual eCTD XML DTD should be changed or altered in any
way.
The maximum length of the name of a single folder or file is 64 characters including the extension. Folder
or file names should be written in lower case only. All files should have one and only one file extension.
The file extension should be used to indicate the format of the file. More details on the naming conventions
are given in Appendix 2, and examples in Appendix 4.
Typically, the file name would be the applicants internal numbering or naming convention for the studies.
The following table gives an example how files could be named.
Table 3-1
Description

File Name

Study Report 1

study-report-1.pdf

Study Report 2

study-report-2.pdf

Study Report n

study-report-n.pdf

Screenshots and Folder Hierarchy


Screenshots are provided in the following chapters for all modules down to the level of hierarchy as
described in this appendix. The representation in module 3 is in alphabetical order due to the nature of the
computer operating system and is therefore not entirely consistent with the sequence of the CTD. In a Web
browser the content will appear in the order of the CTD table of contents.

Regulatory authorities should be notified of additions and changes to the folder structure according to
regional guidance.

Page 3-1

Detailed options on the folders and files are provided in Appendix 4 in case the applicant chooses to submit
more granular documents. It is not mandatory to use the full folder hierarchy. Empty directories can be
omitted; however, when the content is expected justification should be provided why it is missing.

Module 1 Administrative Information and Prescribing Information


The name of the folder for module 1 should be m1.
This module contains administrative information that is unique for each region. Regional guidance will
provide the specific instructions on how to provide the administrative forms and detailed prescribing
information. Please refer to Appendix 5 when preparing module 1.

Module 2 Summaries
The files in this module should be provided as PDF text with the exception of a few embedded images,
when needed. The name of the folder for module 2 should be m2. The folders in module 2 should be named
as follows.
Table 3-2
Section in
CTD

Description

Folder Name

2.2

Introduction

22-intro

2.3

Quality overall summary

23-qos

2.4

Nonclinical Overview

24-nonclin-over

2.5

Clinical Overview

25-clin-over

2.6

Nonclinical Written and Tabulated


Summaries

26-nonclin-sum

2.7

Clinical summary

27-clin-sum

The folder hierarchy for module 2 is presented in the screenshot in figure 3-1.
Figure 3-1 Screenshot of the folder structure of module 2

Module 3 Quality
The name of the folder for module 3 should be m3. The folders in module 3 should be named as follows.
Table 3-3
Section in
CTD

Page 3-2

Description

Folder Name

Section in
CTD

Description

Folder Name

3.2

Body of Data

32-body-data

3.2.S

Drug Substance

32s-drug-sub

3.2.S

Drug Substance [Drug Substance Name]


[Manufacturer]2

substance-1-manufacturer-1

3.2.S.1

General Information (name, manufacturer)

32s1-gen-info

3.2.S.2

Manufacture (name, manufacturer)

32s2-manuf

3.2.S.3

Characterisation (name, manufacturer)

32s3-charac

3.2.S.4

32s4-contr-drug-sub

3.2.S.4.1

Control of Drug Substance (name,


manufacturer)
Specification (name, manufacturer)

3.2.S.4.2

Analytical Procedures (name, manufacturer)

32s42- analyt-proc

3.2.S.4.3

Validation of Analytical Procedures (name,


manufacturer)
Batch Analyses (name, manufacturer)

32s43-val-analyt-proc

3.2.S.4.4
3.2.S.4.5

32s41-spec

32s44-batch-analys

3.2.S.7

Justification of Specification (name,


manufacturer)
Reference Standards or Materials (name,
manufacturer)
Container Closure System (name,
manufacturer)
Stability (name, manufacturer)

3.2.P

Drug Product (name, dosage form)3

32p-drug-prod

3.2.P

Drug Product (name, dosage form) - Name

product-1

3.2.P.1

32p1-desc-comp

3.2.P.3

Description and Composition of the Drug


Product (name, dosage form)
Pharmaceutical Development (name, dosage
form)
Manufacture (name, dosage form)

3.2.P.4

Control of Excipients (name, dosage form)

32p4-contr-excip

3.2.P.4

Control of Excipients (name, dosage form) Excipient 1


Control of Drug Product (name, dosage form)

excipient-1

3.2.S.5
3.2.S.6

3.2.P.2

3.2.P.5
2

32s45-justif-spec
32s5-ref-stand
32s6-cont-closure-sys
32s7-stab

32p2-pharm-dev
32p3-manuf

32p5-contr-drug-prod

Each drug substance-manufacturer should be placed in a separate subordinate folder. Folders and files
should be created for each drug substance-manufacturer section included in the submission in accordance
with the hierarchy identified in the following chapters.
3
Each drug product should be placed in a separate subordinate folder. Folders and files should be created
for each drug product section included in the submission in accordance with the hierarchy identified in the
following chapters. Reference should be made to regional guidance to determine whether the inclusion of
multiple products within a single application is considered appropriate.

Page 3-3

Section in
CTD

Description

Folder Name

3.2.P.5.1

Specification(s) (name, dosage form)

32p51-spec

3.2.P.5.2

Analytical Procedures (name, dosage form)

32p52-analyt-proc

3.2.P.5.3

Validation of Analytical Procedures (name,


dosage form)
Batch Analyses (name, dosage form)

32p53-val-analyt-proc

3.2.P.5.4
3.2.P.5.5

32p54-batch-analys
32p55-charac-imp

3.2.P.7

Characterisation of Impurities (name, dosage


form)
Justification of Specifications (name, dosage
form)
Reference Standards or Materials (name, dosage
form)
Container Closure System (name, dosage form)

3.2.P.8

Stability (name, dosage form)

32p8-stab

3.2.A

Appendices

32a-app

3.2.A.1

Facilities and Equipment (name, manufacturer)

32a1-fac-equip

3.2.A.2

32a2-advent-agent

3.2.A.3

Adventitious Agents Safety Evaluation (name,


dosage form, manufacturer)
Excipients- Name 4

3.2.R

Regional Information5

32r-reg-info

3.3

Literature References

33-lit-ref

3.2.P.5.6
3.2.P.6

32p56-justif-spec
32p6-ref-stand
32p7-cont-closure-sys

32a3-excip-name-1

The folder name should include the name of the excipient, abbreviated as necessary to remain within the
64 character limit.
5
This folder should be included where regional information is appropriate. Reference should be made to
regional guidance for the types of information to be included in this section.

Page 3-4

The folder hierarchy for module 3 is presented in the screenshot in figure 3-2.
Figure 3-2 Screenshot of the folder structure of module 3

Module 4 Nonclinical Study Reports


The name of the folder for module 4 should be m4. The folders in module 4 should be named as follows.
Table 3-4
Section in
CTD
4.2

Page 3-5

Description
Study Reports

Folder Name
42-stud-rep

Section in
CTD

Description

Folder Name

4.2.1

Pharmacology

421-pharmacol

4.2.1.1

Primary Pharmacodynamics

4211-prim-pd

4.2.1.2

Secondary Pharmacodynamics

4212-sec-pd

4.2.1.3

Safety Pharmacology

4213-safety-pharmacol

4.2.1.4

Pharmacodynamic Drug Interactions

4214-pd-drug-interact

4.2.2

Pharmacokinetics

422-pk

4.2.2.1

Analytical Methods and Validation Reports (if


separate reports are available)

4221-analyt-met-val

4.2.2.2

Absorption

4222-absorp

4.2.2.3

Distribution

4223-distrib

4.2.2.4

Metabolism

4224-metab

4.2.2.5

Excretion

4225-excr

4.2.2.6

Pharmacokinetic Drug Interactions (nonclinical)

4226-pk-drug-interact

4.2.2.7

Other Pharmacokinetic Studies

4227-other-pk-stud

4.2.3

Toxicology

423-tox

4.2.3.1

Single-Dose Toxicity (in order by species, by


route)

4231-single-dose-tox

4.2.3.2

Repeat-Dose Toxicity (in order by species, by


route, by duration, including supportive
toxicokinetics evaluations)

4232-repeat-dose-tox

4.2.3.3

Genotoxicity

4233-genotox

4.2.3.3.1

In vitro

42331-in-vitro

4.2.3.3.2

In vivo (including supportive toxicokinetics


evaluations)

42332-in-vivo

4.2.3.4

Carcinogenicity (including supportive


toxicokinetics evaluations)

4234-carcigen

4.2.3.4.1

Long-term studies (in order by species,


including range-finding studies that cannot be
appropriately included under repeat-dose
toxicity or pharmacokinetics)

42341-lt-stud

4.2.3.4.2

Short-or medium-term studies (including rangefinding studies that cannot be appropriately


included under repeat-dose toxicity or
pharmacokinetics)

42342-smt-stud

Page 3-6

Section in
CTD

Description

Folder Name

4.2.3.4.3

Other studies

42343-other-stud

4.2.3.5

Reproductive and Developmental Toxicity


(including range-finding studies and supportive
toxicokinetics evaluations)(If modified study
designs are used, the following subheadings
should be modified accordingly)

4235-repro-dev-tox

4.2.3.5.1

Fertility and early embryonic development

42351-fert-embryo-dev

4.2.3.5.2

Embryo-fetal development

42352-embryo-fetal-dev

4.2.3.5.3

Prenatal and postnatal development, including


maternal function

42353-pre-postnatal-dev

4.2.3.5.4

Studies in which the offspring (juvenile


animals) are dosed and/or further evaluated

42354-juv

4.2.3.6

Local Tolerance

4236-loc-tol

4.2.3.7

Other Toxicity Studies (if available)

4237-other-tox-stud

4.2.3.7.1

Antigenicity

42371-antigen

4.2.3.7.2

Immunotoxicity

42372-immunotox

4.2.3.7.3

Mechanistic studies (if not included elsewhere)

42373-mechan-stud

4.2.3.7.4

Dependence

42374-dep

4.2.3.7.5

Metabolites

42375-metab

4.2.3.7.6

Impurities

42376-imp

4.2.3.7.7

Other

42377-other

4.3

Literature References

43-lit-ref

The folder hierarchy for module 4 is presented in the screenshot in figure 3-3.

Page 3-7

Figure 3-3 Screenshot of the folder structure of module 4

Module 5 Clinical Study Reports


The name of the folder for module 5 should be m5. The folders in module 5 should be named as follows.
Table 3-5
Section in
CTD
5.2

Page 3-8

Description
Tabular Listing of all Clinical Studies

Folder Name
52-tab-list

Section in
CTD

Description

Folder Name

5.3

Clinical Study Reports

53-clin-stud-rep

5.3.1

Reports of Biopharmaceutic Studies

531-rep-biopharm-stud

5.3.1.1

Bioavailability (BA) Study Reports

5311-ba-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Comparative BA and Bioequivalence (BE)


Study Reports

5312-compar-ba-be-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

In vitro In vivo Correlation Study Reports

5313-in-vitro-in-vivo-corr-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Reports of Bioanalytical and Analytical


Methods for Human Studies

5314-bioanalyt-analyt-met

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

5.3.2

Reports of Studies Pertinent to


Pharmacokinetics using Human Biomaterials

532-rep-stud-pk-human-biomat

5.3.2.1

Plasma Protein Binding Study Reports

5321-plasma-prot-bind-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Reports of Hepatic Metabolism and Drug


Interaction Studies

5322-rep-hep-metab-interact-stud

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

5.3.1.2

5.3.1.3

5.3.1.4

5.3.2.2

Page 3-9

Section in
CTD

Description

Folder Name

"Study Report 3"

study-report-3

Reports of Studies Using Other Human


Biomaterials

5323-stud-other-human-biomat

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

5.3.3

Reports of Human Pharmacokinetic (PK)


Studies

533-rep-human-pk-stud

5.3.3.1

Healthy Subject PK and Initial Tolerability


Study Reports

5331-healthy-subj-pk-init-tol-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Patient PK and Initial Tolerability Study


Reports

5332-patient-pk-init-tol-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Intrinsic Factor PK Study Reports

5333-intrin-factor-pk-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Extrinsic Factor PK Study Reports

5334-extrin-factor-pk-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Population PK Study Reports

5335-popul-pk-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

5.3.2.3

5.3.3.2

5.3.3.3

5.3.3.4

5.3.3.5

Page 3-10

Section in
CTD

Description

Folder Name

5.3.4

Reports of Human Pharmacodynamic (PD)


Studies

534-rep-human-pd-stud

5.3.4.1

Healthy Subject PD and PK/PD Study Reports

5341-healthy-subj-pd-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Patient PD and PK/PD Study Reports

5342-patient-pd-stud-rep

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

5.3.4.2

535-rep-effic-safety-stud

5.3.5

Reports of Efficacy and Safety Studies

5.3.5

Reports of Efficacy and Safety Studies


Indication Name

indication-1

5.3.5.1

Study Reports of Controlled Clinical Studies


Pertinent to the Claimed Indication

5351-stud-rep-contr

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Study Reports of Uncontrolled Clinical Studies

5352-stud-rep-uncontr

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Reports of Analyses of Data from More than


One Study

5353-rep-analys-data-more-one-stud

"Study Report 1"

study-report-1

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

Other Study Reports

5354-other-stud-rep

"Study Report 1"

study-report-1

5.3.5.2

5.3.5.3

5.3.5.4

Page 3-11

Section in
CTD

Description

Folder Name

"Study Report 2"

study-report-2

"Study Report 3"

study-report-3

5.3.6

Reports of Postmarketing Experience

536-postmark-exp

5.3.7

Case Report Forms and Individual Patient


Listings6

537-crf-ipl

Study Report 1

study-report-1

Study Report 2

study-report-2

Study Report 3

study-report-3

Literature References

54-lit-ref

5.4

This folder contains as many folders as studies are included that have included case report forms and/or
individual patient listings. The folders should be named like the corresponding study. The content of the
folders should follow regional guidance.

Page 3-12

The folder hierarchy for module 5 is presented in the screenshot in figure 3-4.
Figure 3-4 Screenshot of the folder structure of module 5

Figure 3-4 Screenshot of the folder structure of module 5 (cont)

Page 3-13

Page 3-14

Figure 3-4 Screenshot of the folder structure of module 5 (cont)

Page 3-15

Comment

Number
Title
Element
File/Directory

Each item in the table has a unique sequentially assigned reference number. These reference numbers can
change with each version of this appendix.
CTD section number
CTD title
Element name in the Backbone
Relative path of the File/Directory. The file extension corresponds to the file type; i.e., the pdf extension is
only illustrative. Refer to Table 6.1, Appendix 6, for details for the head of the path name
Comments

Page 4-1

Where file names are presented in italics applicants would substitute these with file names in accordance with their own naming conventions.

The file organization table covers files that constitute the backbone itself plus necessary additional files to make the submission complete, readable and
processable. The file names are not mandatory, but highly recommended. Refer to the M4 Organisation Document: Granularity Annex for information on where
multiple documents/files are allowed in each section or subsection of the eCTD.

Sequential
number

Each item in the file organization table that is listed in this appendix includes the information outlined below:

Appendix 4: File Organization for the eCTD

Page 4-2

Number
Title
Element
File
Comment
Number
Title
Element
File
Comment

index-md5.txt
The MD5 of the Backbone

index.xml
This is the Backbone

Table 4-1

1
Administrative Information and Prescribing Information
m1-administrative-information-and-prescribing-information
m1
Only one of the regional directories is needed

Page 4-3

m1/eu
EU directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to regional
Comment
guidance for details
Number
Title
Element
Directory m1/jp
Japan directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to
Comment
regional guidance for details
Number
Title
Element
Directory m1/us
US directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to regional
Comment
guidance for details
Number
Title
Element
Directory m1/xx
xx directory; where xx is a two character country code from ISO-3166-1. In addition to the appropriate regional documents, the regional
Comment
xml instance should be located in this folder. Refer to regional guidance for details

Number
Title
Element
Directory
Comment
Number
Title
Element
Directory

2.2
Introduction
m2-2-introduction
m2/22-intro/introduction.pdf

2.2
Introduction
m2-2-introduction
m2/22-intro

2
Common Technical Document Summaries
m2-common-technical-document-summaries
m2

Page 4-4

2.3
Quality Overall Summary
m2-3-quality-overall-summary
m2/23-qos
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Comment
Overall Summary
Number
2.3
Title
Introduction
12 Element
m2-3-introduction
File
m2/23-qos/introduction.pdf
Comment
13 Number
2.3.S
Title
Drug Substance - Name - Manufacturer
Element
m2-3-s-drug-substance
File
m2/23-qos/drug-substance.pdf

Number
Title
8 Element
Directory
Comment
Number
Title
9 Element
Directory
Comment
Number
Title
10 Element
File
Comment
Number
Title
Element
11
Directory

Page 4-5

2.3.P
Drug Product -Name
m2-3-p-drug-product
m2/23-qos/drug-product-name.pdf
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Overall Summary
14
he file name should always include the name of the drug product through inclusion of the name of the form/strength to give e.g., 'drugproduct-tablet-5mg'.
Comment
Where the application is for a complex presentation with multiple components the file name should identify additional items such as the
component.
Refer to regional guidance for definition of what constitutes a drug product and the acceptability of more than one drug product in an
application. Where more than one drug product is acceptable in an application, a separate file should be provided for each drug product.
Number
2.3.A
Title
Appendices
Element
m2-3-a-appendices
15
File
m2/23-qos/appendices.pdf
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Comment
Overall Summary
Number
2.3.R
Title
Regional Information
Element
m2-3-r-regional-information
16
File
m2/23-qos/regional-information.pdf
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Comment
Overall Summary
17 Number
2.4

Number
Title
Element
File

Where there are more than one drug substance and/or manufacturer, separate files should be provided for each. The
file name should always include the name of the drug substance e.g., ranitidine hydrochloride through inclusion of
Comment the International Non-proprietary Name to give 'ranitidine-hydrochloride'. Similarly, for manufacturer, the file name
should always include the name of the manufacturer e.g., ranitidine-hydrochloride-manufacturer-1.pdf.
Where there is more than one manufacturer, the drug substance file should be repeated but with an indication of
each manufacturer concerned included in the file name, the first instance e.g., 'drug-substance-1- manufacturer-1.pdf'
and the second 'drug-substance-1-manufacturer-2.pdf'.

Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the
Quality Overall Summary

Nonclinical Overview
m2-4-nonclinical-overview
m2/24-nonclin-over

Page 4-6

2.4
Nonclinical Overview
m2-4-nonclinical-overview
m2/24-nonclin-over/nonclinical-overview.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
Comment
within the document to these sub-headings.
Number
2.5
Title
Clinical Overview
19 Element
m2-5-clinical-overview
Directory m2/25-clin-over
Comment
Number
2.5
Title
Clinical Overview
Element
m2-5-clinical-overview
20
File
m2/25-clin-over/clinical-overview.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
Comment
within the document to these sub-headings.
Number
2.6
Title
Nonclinical Written and Tabulated Summaries
21 Element
m2-6-nonclinical-written-and-tabulated-summaries
Directory m2/26-nonclin-sum
Comment
Number
2.6.1
Title
Introduction
22 Element
m2-6-1-introduction
File
m2/26-nonclin-sum/introduction.pdf
Comment
23 Number
2.6.2
Title
Pharmacology Written Summary
Element
m2-6-2-pharmacology-written-summary
File
m2/26-nonclin-sum/pharmacol-written-summary.pdf

Title
Element
Directory
Comment
Number
Title
Element
18
File

Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.6.3
Pharmacology Tabulated Summary
m2-6-3-pharmacology-tabulated-summary
m2/26-nonclin-sum/pharmacol-tabulated-summary.pdf
Should have further navigation via bookmarks
2.6.4
Pharmacokinetics Written Summary
m2-6-4-pharmacokinetics-written-summary
m2/26-nonclin-sum/pharmkin-written-summary.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.6.5
Pharmacokinetics Tabulated Summary
m2-6-5-pharmacokinetics-tabulated-summary
m2/26-nonclin-sum/pharmkin-tabulated-summary.pdf
Should have further navigation via bookmarks
2.6.6
Toxicology Written Summary
m2-6-6-toxicology-written-summary
m2/26-nonclin-sum/toxicology-written-summary.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.6.7
Toxicology Tabulated Summary
m2-6-7-toxicology-tabulated-summary
m2/26-nonclin-sum/toxicology-tabulated-summary.pdf
Should have further navigation via bookmarks
2.7
Clinical Summary
m2-7-clinical-summary
m2/27-clin-sum

Page 4-7

Number
Title
28 Element
File
Comment
Number
Title
29 Element
Directory
Comment
30 Number
2.7.1

Comment

Number
Title
26 Element
File
Comment
Number
Title
Element
27
File

Comment

Number
Title
24 Element
File
Comment
Number
Title
Element
25
File

Comment

Comment

Page 4-8

Number
Title
34 Element
File
Comment
35 Number
Title
Element
File

Comment

Number
Title
Element
33
File

32

Number
Title
Element
File

Comment

Number
Title
Element
31
File

Comment

Title
Element
File

2.7.6
Synopses of Individual Studies
m2-7-6-synopses-of-individual-studies
m2/27-clin-sum/synopses-indiv-studies.pdf

Summary of Biopharmaceutic Studies and Associated Analytical Methods


m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analytical-methods
m2/27-clin-sum/summary-biopharm.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.7.2
Summary of Clinical Pharmacology Studies
m2-7-2-summary-of-clinical-pharmacology-studies
m2/27-clin-sum/summary-clin-pharm.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.7.3
Summary of Clinical Efficacy Indication
m2-7-3-summary-of-clinical-efficacy
m2/27-clin-sum/summary-clin-efficacy-indication.pdf
The file name should always include the indication being claimed (abbreviated if appropriate) e.g., 'summary-clin-efficacy-asthma'. Where
there is more than one indication (e.g., asthma & migraine) then the first indication has a file name 'summary-clin-efficacy-asthma' and the
second 'summary-clin-efficacy-migraine'.
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.7.4
Summary of Clinical Safety
m2-7-4-summary-of-clinical-safety
m2/27-clin-sum/summary-clin-safety.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.7.5
Literature References
m2-7-5-literature-references
m2/27-clin-sum/literature-references.pdf

Page 4-9

Comment

These synopses should already be located in the Clinical Study Reports in Module 5 and should not, therefore, be repeated in Module 2. It is
considered sufficient to provide hyperlinks from the listing of the studies, located here, to the locations of the synopses in Module 5.

39

38

37

36

Page 4-10

Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory

3.2.S
Drug Substance - Drug Substance Name - Manufacturer
m3-2-s-drug-substance
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1

3.2.S
Drug Substance
m3-2-s-drug-substance
m3/32-body-data/32s-drug-sub

3
Quality
m3-quality
m3
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for Module 3
3.2
Body of Data
m3-2-body-of-data
m3/32-body-data

43

42

41

40

Page 4-11

Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number

Comment

3.2.S.1.3

3.2.S.1.2
Structure (name, manufacturer)
m3-2-s-1-2-structure
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/structure.pdf

3.2.S.1.1
Nomenclature (name, manufacturer)
m3-2-s-1-1-nomenclature
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/nomenclature.pdf

Typically the applicant would include the specific manufacturer(s) (and/or site) in the folder name.
3.2.S.1
General Information (name, manufacturer)
m3-2-s-1-general-information
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info

In this example a set of folders can include:


ranitidine-hydrochloride-manufacturer-1
ranitidine-hydrochloride-manufacturer-2
cimetidine-hydrochloride-manufacturer-1
cimetidine-hydrochloride-manufacturer-2

Where there is more than one drug substance (e.g., ranitidine hydrochloride and cimetidine) then the first drug
substance has a folder 'ranitidine-hydrochloride' and the second 'cimetidine'.

Where there is more than one manufacturer, the drug substance folder should be repeated but with an indication of
each manufacturer concerned included in the folder name, the first instance e.g., 'drug-substance-1- manufacturer-1'
and the second 'drug-substance-1-manufacturer-2'.

The folder name should always include the name of the drug substance e.g., ranitidine through inclusion of the
International Non-proprietary Name to give 'ranitidine-hydrochloride'. Similarly, for manufacturer, the folder name
should always include the name of the manufacturer e.g., ranitidine-manufacturer-1.

49

48

47

46

45

44

Page 4-12

Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment

3.2.S.2.5
Process Validation and/or Evaluation (name, manufacturer)
m3-2-s-2-5-process-validation-and-or-evaluation
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/process-validation.pdf

3.2.S.2.4
Controls of Critical Steps and Intermediates (name, manufacturer)
m3-2-s-2-4-controls-of-critical-steps-and-intermediates
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/control-critical-steps.pdf

3.2.S.2.3
Control of Materials (name, manufacturer)
m3-2-s-2-3-control-of-materials
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/control-of-materials.pdf

3.2.S.2.1
Manufacturer(s) (name, manufacturer)
m3-2-s-2-1-manufacturer
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manufacturer.pdf
For this document there should be only information regarding one manufacturer
3.2.S.2.2
Description of Manufacturing Process and Process Controls (name, manufacturer)
m3-2-s-2-2-description-of-manufacturing-process-and-process-controls
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manuf-process-and-controls.pdf

Manufacture (name, manufacturer)


m3-2-s-2-manufacture
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf

3.2.S.2

General Properties (name, manufacturer)


m3-2-s-1-3-general-properties
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/general-properties.pdf

56

55

54

53

52

51

50

Page 4-13

Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment

3.2.S.4.1
Specification (name, manufacturer)
m3-2-s-4-1-specification
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s41-spec/specification.pdf

3.2.S.4.1
Specification (name, manufacturer)
m3-2-s-4-1-specification
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s41-spec

3.2.S.4
Control of Drug Substance (name, manufacturer)
m3-2-s-4-control-of-drug-substance
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub

3.2.S.3.2
Impurities (name, manufacturer)
m3-2-s-3-2-impurities
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac/impurities.pdf

3.2.S.3.1
Elucidation of Structure and Other Characteristics (name, manufacturer)
m3-2-s-3-1-elucidation-of-structure-and-other-characteristics
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac/elucidation-of-structure.pdf

3.2.S.3
Characterisation (name, manufacturer)
m3-2-s-3-characterisation
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac

3.2.S.2.6
Manufacturing Process Development (name, manufacturer)
m3-2-s-2-6-manufacturing-process-development
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manuf-process-development.pdf

63

62

61

60

59

58

57

Page 4-14

Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File

3.2.S.4.3.2
Validation of Analytical Procedure-2
m3-2-s-4-3-validation-of-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc/validation-analyt-procedure-2.pdf

3.2.S.4.3
Validation of Analytical Procedures
m3-2-s-4-3-validation-of-analytical-procedures (name, manufacturer)
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
3.2.S.4.3.1
Validation of Analytical Procedure-1
m3-2-s-4-3-validation-of-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc/validation-analyt-procedure-1.pdf

3.2.S.4.2.3
Analytical Procedure-3
m3-2-s-4-2-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc/analytical-procedure-3.pdf

3.2.S.4.2.2
Analytical Procedure-2
m3-2-s-4-2-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc/analytical-procedure-2.pdf

The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
3.2.S.4.2.1
Analytical Procedure-1
m3-2-s-4-2-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc/analytical-procedure-1.pdf

3.2.S.4.2
Analytical Procedures (name, manufacturer)
m3-2-s-4-2-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc

70

69

68

67

66

65

64

Page 4-15

Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element

3.2.S.5
Reference Standards or Materials (name, manufacturer)
m3-2-s-5-reference-standards-or-materials

3.2.S.5
Reference Standards or Materials (name, manufacturer)
m3-2-s-5-reference-standards-or-materials
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand

3.2.S.4.5
Justification of Specification (name, manufacturer)
m3-2-s-4-5-justification-of-specification
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s45-justif-spec/justification-of-specification.pdf

3.2.S.4.5
Justification of Specification (name, manufacturer)
m3-2-s-4-5-justification-of-specification
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s45-justif-spec

3.2.S.4.4
Batch Analyses (name, manufacturer)
m3-2-s-4-4-batch-analyses
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s44-batch-analys/batch-analyses.pdf

3.2.S.4.4
Batch Analyses (name, manufacturer)
m3-2-s-4-4-batch-analyses
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s44-batch-analys

3.2.S.4.3.3
Validation of Analytical Procedure-3
m3-2-s-4-3-validation-of-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc/validation-analyt-procedure-3.pdf

77

76

75

74

73

72

71

Page 4-16

File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element

3.2.P
Drug Product (name, dosage form)
m3-2-p-drug-product

3.2.S.7.3
Stability Data (name, manufacturer)
m3-2-s-7-3-stability-data
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/stability-data.pdf

3.2.S.7.2
Post-approval Stability Protocol and Stability Commitment (name, manufacturer)
m3-2-s-7-2-post-approval-stability-protocol-and-stability-commitment
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/postapproval-stability.pdf

3.2.S.7.1
Stability Summary and Conclusions (name, manufacturer)
m3-2-s-7-1-stability-summary-and-conclusions
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/stability-summary.pdf

3.2.S.7
Stability (name, manufacturer)
m3-2-s-7-stability
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab

3.2.S.6
Container Closure System (name, manufacturer)
m3-2-s-6-container-closure-system
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys/container-closure-system.pdf

m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand/reference-standards.pdf
Where a multiple file approach is taken for this section, the file names should indicate which reference standard is covered in the document.
3.2.S.6
Container Closure System (name, manufacturer)
m3-2-s-6-container-closure-system
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys

82

81

80

79

78

Page 4-17

Comment

Number
Title
Element
File

Comment

Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory

Comment

Comment
Number
Title
Element
Directory

Directory

Development section.

Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical

3.2.P.2
Pharmaceutical Development (name, dosage form)
m3-2-p-2-pharmaceutical-development
m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev
Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical
Development section.
3.2.P.2
Pharmaceutical Development (name, dosage form)
m3-2-p-2-pharmaceutical-development
m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev/pharmaceutical-development.pdf

3.2.P.1
Description and Composition of the Drug Product (name, dosage form)
m3-2-p-1-description-and-composition-of-the-drug-product
m3/32-body-data/32p-drug-prod/product-1/32p1-desc-comp/description-and-composition.pdf

m3-2-p-drug-product
m3/32-body-data/32p-drug-prod/product-1
The folder name should always include the name of the drug product through inclusion of the name of the form/strength to give e.g., 'tablet5mg'. Where there is more than one drug product (e.g., powder for reconstitution and diluent) then the first drug product has a folder
'powder-for-reconstitution' and the second 'diluent'.
Refer to regional guidance for definition of what constitutes a drug product and the acceptability of more than one drug product in an
application.
3.2.P.1
Description and Composition of the Drug Product (name, dosage form)
m3-2-p-1-description-and-composition-of-the-drug-product
m3/32-body-data/32p-drug-prod/product-1/32p1-desc-comp

3.2.P
Drug Product (name, dosage form) Name

m3/32-body-data/32p-drug-prod

89

88

87

86

85

84

83

Page 4-18

Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory

3.2.P.3.5
Process Validation and/or Evaluation (name, dosage form)
m3-2-p-3-5-process-validation-and-or-evaluation
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/process-validation.pdf
The applicant has the option to submit one or multiple files, one for each validation or evaluation.
3.2.P.4
Control of Excipients (name, dosage form)
m3-2-p-4-control-of-excipients
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip

3.2.P.3.4
Controls of Critical Steps and Intermediates (name, dosage form)
m3-2-p-3-4-controls-of-critical-steps-and-intermediates
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/control-critical-steps.pdf

3.2.P.3.3
Description of Manufacturing Process and Process Controls (name, dosage form)
m3-2-p-3-3-description-of-manufacturing-process-and-process-controls
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manuf-process-and-controls.pdf

3.2.P.3.2
Batch Formula (name, dosage form)
m3-2-p-3-2-batch-formula
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/batch-formula.pdf

3.2.P.3.1
Manufacturer(s) (name, dosage form)
m3-2-p-3-1-manufacturers
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manufacturers.pdf

Manufacture (name, dosage form)


m3-2-p-3-manufacture
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf

3.2.P.3

96

95

94

93

92

91

90

Page 4-19

Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number

Comment

Comment
Number
Title
Element
Directory

3.2.P.4.6

3.2.P.4
Control of Excipients (name, dosage form) Excipient
m3-2-p-4-control-of-excipients
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1
For a drug product containing more than one excipient, the information requested for sections 3.2.P.4.1 3.2.P.4.4 should be provided in its
entirety for each excipient. For compendial excipient(s) without additional specification tests, it is appropriate to have all information in
one file, making sure to introduce a folder for each of new documents to avoid mixing files and folders at the same level. Non-compendial
excipients should follow the structure outlined below.
3.2.P.4.1
Specifications (name, dosage form)
m3-2-p-4-1-specifications
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/specifications.pdf
See comment under 3.2.P.4.
3.2.P.4.2
Analytical Procedures (name, dosage form)
m3-2-p-4-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/analytical-procedures.pdf
See comment under 3.2.P.4.
3.2.P.4.3
Validation of Analytical Procedures (name, dosage form)
m3-2-p-4-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/validation-analyt-procedures.pdf
See comment under 3.2.P.4.
3.2.P.4.4
Justification of Specifications (name, dosage form)
m3-2-p-4-4-justification-of-specifications
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/justification-of-specifications.pdf
See comment under 3.2.P.4.
3.2.P.4.5
Excipients of Human or Animal Origin (name, dosage form)
m3-2-p-4-5-excipients-of-human-or-animal-origin
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipients-human-animal.pdf

Page 4-20

Title
Element
File
Comment
Number
Title
97 Element
Directory
Comment
Number
Title
98 Element
Directory
Comment
Number
Title
99 Element
File
Comment
Number
Title
100 Element
Directory
Comment
Number
Title
101 Element
File
Comment
Number
Title
102 Element
File
Comment

3.2.P.5.2.2
Analytical Procedure 2
m3-2-p-5-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-2.pdf

3.2.P.5.2
Analytical Procedures (name, dosage form)
m3-2-p-5-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
3.2.P.5.2.1
Analytical Procedure 1
m3-2-p-5-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-1.pdf

3.2.P.5.1
Specification(s) (name, dosage form)
m3-2-p-5-1-specifications
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec/specifications.pdf

3.2.P.5.1
Specification(s) (name, dosage form)
m3-2-p-5-1-specifications
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec

m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod

3.2.P.5
Control of Drug Product (name, dosage form)
m3-2-p-5-control-of-drug-product

Novel Excipients (name, dosage form)


m3-2-p-4-6-novel-excipients
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/novel-excipients.pdf

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106

105

104

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3.2.P.5.4
Batch Analyses (name, dosage form)
m3-2-p-5-4-batch-analyses
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p54-batch-analys/batch-analyses.pdf

3.2.P.5.4
Batch Analyses (name, dosage form)
m3-2-p-5-4-batch-analyses
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p54-batch-analys

3.2.P.5.3.3
Validation of Analytical Procedures 3
m3-2-p-5-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc/validation-analytical-procedures-3.pdf

3.2.P.5.3.2
Validation of Analytical Procedures 2
m3-2-p-5-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc/validation-analytical-procedures-2.pdf

3.2.P.5.3.1
Validation of Analytical Procedures 1
m3-2-p-5-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc/validation-analytical-procedures-1.pdf

3.2.P.5.3
Validation of Analytical Procedures (name, dosage form)
m3-2-p-5-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.

3.2.P.5.2.3
Analytical Procedure 3
m3-2-p-5-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-3.pdf

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3.2.P.6
Reference Standards or Materials (name, dosage form)
m3-2-p-6-reference-standards-or-materials
m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand/reference-standards.pdf
When a multiple file approach is taken for this section, the file names should indicate which reference standard is covered in the document.
3.2.P.7
Container Closure System (name, dosage form)
m3-2-p-7-container-closure-system
m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys

3.2.P.6
Reference Standards or Materials (name, dosage form)
m3-2-p-6-reference-standards-or-materials
m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand

3.2.P.5.6
Justification of Specifications (name, dosage form)
m3-2-p-5-6-justification-of-specifications
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec/justification-of-specifications.pdf

3.2.P.5.6
Justification of Specifications (name, dosage form)
m3-2-p-5-6-justification-of-specifications
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec

3.2.P.5.5
Characterisation of Impurities (name, dosage form)
m3-2-p-5-5-characterisation-of-impurities
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p55-charac-imp/characterisation-impurities.pdf

3.2.P.5.5
Characterisation of Impurities (name, dosage form)
m3-2-p-5-5-characterisation-of-impurities
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p55-charac-imp

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3.2.A.1
Facilities and Equipment (name, manufacturer)
m3-2-a-1-facilities-and-equipment
m3/32-body-data/32a-app/32a1-fac-equip

3.2.A
Appendices
m3-2-a-appendices
m3/32-body-data/32a-app

3.2.P.8.3
Stability Data (name, dosage form)
m3-2-p-8-3-stability-data
m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-data.pdf

3.2.P.8.2
Post-approval Stability Protocol and Stability Commitment (name, dosage form)
m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment
m3/32-body-data/32p-drug-prod/product-1/32p8-stab/postapproval-stability.pdf

3.2.P.8.1
Stability Summary and Conclusion (name, dosage form)
m3-2-p-8-1-stability-summary-and-conclusion
m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-summary.pdf

3.2.P.8
Stability (name, dosage form)
m3-2-p-8-stability
m3/32-body-data/32p-drug-prod/product-1/32p8-stab

3.2.P.7
Container Closure System (name, dosage form)
m3-2-p-7-container-closure-system
m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys/container-closure-system.pdf

Comment

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126

125

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Comment

3.2.A.2.3

3.2.A.2.2
Adventitious Agents Safety Evaluation Report 2
m3-2-a-2-adventitious-agents-safety-evaluation
m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-2.pdf

3.2.A.2
Adventitious Agents Safety Evaluation (name, dosage form, manufacturer)
m3-2-a-2-adventitious-agents-safety-evaluation
m3/32-body-data/32a-app/32a2-advent-agent
Nonviral adventitious agents reports should be placed in this folder. For viral adventitious agents the following sub-folder structure should
be used. However, where the is more than one drug substance, drug product, manufacturer etc., a directory should be created each option
and its identity included in the directory name.
3.2.A.2.1
Adventitious Agents Safety Evaluation Report 1
m3-2-a-2-adventitious-agents-safety-evaluation
m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-1.pdf

3.2.A.1.3
Facilities and Equipment Report 3
m3-2-a-1-facilities-and-equipment
m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-3.pdf

3.2.A.1.2
Facilities and Equipment Report 2
m3-2-a-1-facilities-and-equipment
m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-2.pdf

Several reports are likely to be included in this appendix. The organisation is left to the applicant to define. However, where there is more
than one manufacturer a folder should be created for each manufacturer and the identity of the manufacturer included in the directory name.
3.2.A.1.1
Facilities and Equipment Report 1
m3-2-a-1-facilities-and-equipment
m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-1.pdf

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3.3.3
Reference 3

3.3.2
Reference 2
m3-3-literature-references
m3/33-lit-ref/reference-2.pdf

The directory/file structure would typically follow that of the drug substance section in Module 3. Refer to Regional guidances for the need
for such information to be included in the submission directly as opposed to its inclusion in a Drug Master File.
3.2.R
Regional Information
m3-2-r-regional-information
m3/32-body-data/32r-reg-info
Refer to the M4 Organisation Document: Granularity Annex for the approach to take with this section.
3.3
Literature References
m3-3-literature-references
m3/33-lit-ref
Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference).
3.3.1
Reference 1
m3-3-literature-references
m3/33-lit-ref/reference-1.pdf

3.2.A.3
Excipients Name
m3-2-a-3-excipients
m3/32-body-data/32a-app/32a3-excip-name-1
The name of any novel excipient should be included in the folder name. If there is more than one novel excipient then each folder should
have unique identification through the use of different names e.g., '32a3-excip-name-1' and '32a3-excip-name-2'.

Adventitious Agents Safety Evaluation Report 3


m3-2-a-2-adventitious-agents-safety-evaluation
m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-3.pdf

Page 4-26

Element
File
Comment

m3-3-literature-references
m3/33-lit-ref/reference-3.pdf

4.2.1.1
Primary Pharmacodynamics
m4-2-1-1-primary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4211-prim-pd

4.2.1
Pharmacology
m4-2-1-pharmacology
m4/42-stud-rep/421-pharmacol

4.2
Study Reports
m4-2-study-reports
m4/42-stud-rep

4
Nonclinical Study Reports
m4-nonclinical-study-reports
m4

Page 4-27

4.2.1.1.1
Study Report 1
m4-2-1-1-primary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-1.pdf
Typically a single file should be provided for each study report 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 file. In this case the text portion of the report should
be one file and the appendices may be one or more files. In choosing the level of granularity for these reports, the applicant should consider
141
that, when relevant information is changed at any point in the product's lifecycle, replacements of complete documents/files should be
provided.
Comment
Where the approach of multiple files is used it is recommended that a directory is created at the study report level and the relevant files
included within the directory.
It is possible to have the additional graphical file(s) inserted directly into the PDF file, thus making management of the file easier.
Alternatively, the applicant can choose to manage graphical files independently.
This comment is applicable to all study reports in Module 4.

140

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4.2.1.3
Safety Pharmacology
m4-2-1-3-safety-pharmacology
m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol

4.2.1.2.3
Study Report 3
m4-2-1-2-secondary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-3.pdf

4.2.1.2.2
Study Report 2
m4-2-1-2-secondary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-2.pdf

4.2.1.2.1
Study Report 1
m4-2-1-2-secondary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-1.pdf

4.2.1.2
Secondary Pharmacodynamics
m4-2-1-2-secondary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4212-sec-pd

4.2.1.1.3
Study Report 3
m4-2-1-1-primary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-3.pdf

4.2.1.1.2
Study Report 2
m4-2-1-1-primary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-2.pdf

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4.2.1.4.3
Study Report 3
m4-2-1-4-pharmacodynamic-drug-interactions
m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-3.pdf

4.2.1.4.2
Study Report 2
m4-2-1-4-pharmacodynamic-drug-interactions
m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-2.pdf

4.2.1.4.1
Study Report 1
m4-2-1-4-pharmacodynamic-drug-interactions
m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-1.pdf

m4-2-1-4-pharmacodynamic-drug-interactions
m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact

4.2.1.4
Pharmacodynamic Drug Interactions

4.2.1.3.3
Study Report 3
m4-2-1-3-safety-pharmacology
m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-3.pdf

4.2.1.3.2
Study Report 2
m4-2-1-3-safety-pharmacology
m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-2.pdf

4.2.1.3.1
Study Report 1
m4-2-1-3-safety-pharmacology
m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-1.pdf

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4.2.2.2.1
Study Report 1
m4-2-2-2-absorption
m4/42-stud-rep/422-pk/4222-absorp/study-report-1.pdf

4.2.2.2
Absorption
m4-2-2-2-absorption
m4/42-stud-rep/422-pk/4222-absorp

4.2.2.1.3
Study Report 3
m4-2-2-1-analytical-methods-and-validation-reports
m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-3.pdf

4.2.2.1.2
Study Report 2
m4-2-2-1-analytical-methods-and-validation-reports
m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-2.pdf

4.2.2.1.1
Study Report 1
m4-2-2-1-analytical-methods-and-validation-reports
m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-1.pdf

4.2.2.1
Analytical Methods and Validation Reports (if separate reports are available)
m4-2-2-1-analytical-methods-and-validation-reports
m4/42-stud-rep/422-pk/4221-analyt-met-val

4.2.2
Pharmacokinetics
m4-2-2-pharmacokinetics
m4/42-stud-rep/422-pk

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4.2.2.4
Metabolism
m4-2-2-4-metabolism
m4/42-stud-rep/422-pk/4224-metab

4.2.2.3.3
Study Report 3
m4-2-2-3-distribution
m4/42-stud-rep/422-pk/4223-distrib/study-report-3.pdf

4.2.2.3.2
Study Report 2
m4-2-2-3-distribution
m4/42-stud-rep/422-pk/4223-distrib/study-report-2.pdf

4.2.2.3.1
Study Report 1
m4-2-2-3-distribution
m4/42-stud-rep/422-pk/4223-distrib/study-report-1.pdf

4.2.2.3
Distribution
m4-2-2-3-distribution
m4/42-stud-rep/422-pk/4223-distrib

4.2.2.2.3
Study Report 3
m4-2-2-2-absorption
m4/42-stud-rep/422-pk/4222-absorp/study-report-3.pdf

4.2.2.2.2
Study Report 2
m4-2-2-2-absorption
m4/42-stud-rep/422-pk/4222-absorp/study-report-2.pdf

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4.2.2.5.3
Study Report 3
m4-2-2-5-excretion

4.2.2.5.2
Study Report 2
m4-2-2-5-excretion
m4/42-stud-rep/422-pk/4225-excr/study-report-2.pdf

4.2.2.5.1
Study Report 1
m4-2-2-5-excretion
m4/42-stud-rep/422-pk/4225-excr/study-report-1.pdf

4.2.2.5
Excretion
m4-2-2-5-excretion
m4/42-stud-rep/422-pk/4225-excr

4.2.2.4.3
Study Report 3
m4-2-2-4-metabolism
m4/42-stud-rep/422-pk/4224-metab/study-report-3.pdf

4.2.2.4.2
Study Report 2
m4-2-2-4-metabolism
m4/42-stud-rep/422-pk/4224-metab/study-report-2.pdf

4.2.2.4.1
Study Report 1
m4-2-2-4-metabolism
m4/42-stud-rep/422-pk/4224-metab/study-report-1.pdf

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4.2.2.7.2
Study Report 2
m4-2-2-7-other-pharmacokinetic-studies

4.2.2.7.1
Study Report 1
m4-2-2-7-other-pharmacokinetic-studies
m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-1.pdf

4.2.2.7
Other Pharmacokinetic Studies
m4-2-2-7-other-pharmacokinetic-studies
m4/42-stud-rep/422-pk/4227-other-pk-stud

4.2.2.6.3
Study Report 3
m4-2-2-6-pharmacokinetic-drug-interactions
m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-3.pdf

4.2.2.6.2
Study Report 2
m4-2-2-6-pharmacokinetic-drug-interactions
m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-2.pdf

4.2.2.6.1
Study Report 1
m4-2-2-6-pharmacokinetic-drug-interactions
m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-1.pdf

4.2.2.6
Pharmacokinetic Drug Interactions (nonclinical)
m4-2-2-6-pharmacokinetic-drug-interactions
m4/42-stud-rep/422-pk/4226-pk-drug-interact

m4/42-stud-rep/422-pk/4225-excr/study-report-3.pdf

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4.2.3.2
Repeat-Dose Toxicity (in order by species, by route, by duration, including supportive toxicokinetics evaluations)

4.2.3.1.3
Study Report 3
m4-2-3-1-single-dose-toxicity
m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-3.pdf

4.2.3.1.2
Study Report 2
m4-2-3-1-single-dose-toxicity
m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-2.pdf

4.2.3.1.1
Study Report 1
m4-2-3-1-single-dose-toxicity
m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-1.pdf

4.2.3.1
Single-Dose Toxicity (in order by species, by route)
m4-2-3-1-single-dose-toxicity
m4/42-stud-rep/423-tox/4231-single-dose-tox

4.2.3
Toxicology
m4-2-3-toxicology
m4/42-stud-rep/423-tox

4.2.2.7.3
Study Report 3
m4-2-2-7-other-pharmacokinetic-studies
m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-3.pdf

m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-2.pdf

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4.2.3.3.1.2
Study Report 2

4.2.3.3.1.1
Study Report 1
m4-2-3-3-1-in-vitro
m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-1.pdf

4.2.3.3.1
In vitro
m4-2-3-3-1-in-vitro
m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro

4.2.3.3
Genotoxicity
m4-2-3-3-genotoxicity
m4/42-stud-rep/423-tox/4233-genotox

4.2.3.2.3
Study Report 3
m4-2-3-2-repeat-dose-toxicity
m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-3.pdf

4.2.3.2.2
Study Report 2
m4-2-3-2-repeat-dose-toxicity
m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-2.pdf

4.2.3.2.1
Study Report 1
m4-2-3-2-repeat-dose-toxicity
m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-1.pdf

m4-2-3-2-repeat-dose-toxicity
m4/42-stud-rep/423-tox/4232-repeat-dose-tox

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203

202

201

200

199

198

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4.2.3.4.1

4.2.3.4
Carcinogenicity (including supportive toxicokinetics evaluations)
m4-2-3-4-carcinogenicity
m4/42-stud-rep/423-tox/4234-carcigen

4.2.3.3.2.3
Study Report 3
m4-2-3-3-2-in-vivo
m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-3.pdf

4.2.3.3.2.2
Study Report 2
m4-2-3-3-2-in-vivo
m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-2.pdf

4.2.3.3.2.1
Study Report 1
m4-2-3-3-2-in-vivo
m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-1.pdf

4.2.3.3.2
In vivo (including supportive toxicokinetics evaluations)
m4-2-3-3-2-in-vivo
m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo

4.2.3.3.1.3
Study Report 3
m4-2-3-3-1-in-vitro
m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-3.pdf

m4-2-3-3-1-in-vitro
m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-2.pdf

Title

Page 4-37

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209 Element
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210 Number
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208

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205 Element
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206 Element
File
Comment
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207 Element
File
Comment
Number

Title

4.2.3.4.2.2
Study Report 2
m4-2-3-4-2-short-or-medium-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-2.pdf

4.2.3.4.2.1
Study Report 1
m4-2-3-4-2-short-or-medium-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-1.pdf

4.2.3.4.2
Short- or medium-term studies (including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
pharmacokinetics)
m4-2-3-4-2-short-or-medium-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud

4.2.3.4.1.3
Study Report 3
m4-2-3-4-1-long-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-3.pdf

4.2.3.4.1.2
Study Report 2
m4-2-3-4-1-long-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-2.pdf

4.2.3.4.1.1
Study Report 1
m4-2-3-4-1-long-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-1.pdf

Long-term studies (in order by species, including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
pharmacokinetics)
m4-2-3-4-1-long-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud

Title

4.2.3.5
Reproductive and Developmental Toxicity (including range-finding studies and supportive toxicokinetics evaluations) (If modified study
designs are used, the following subheadings should be modified accordingly)
m4-2-3-5-reproductive-and-developmental-toxicity
m4/42-stud-rep/423-tox/4235-repro-dev-tox

4.2.3.4.3.3
Study Report 3
m4-2-3-4-3-other-studies
m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-3.pdf

4.2.3.4.3.2
Study Report 2
m4-2-3-4-3-other-studies
m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-2.pdf

4.2.3.4.3.1
Study Report 1
m4-2-3-4-3-other-studies
m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-1.pdf

4.2.3.4.3
Other studies
m4-2-3-4-3-other-studies
m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud

4.2.3.4.2.3
Study Report 3
m4-2-3-4-2-short-or-medium-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-3.pdf

Page 4-38

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217 Number
4.2.3.5.1
Title
Fertility and early embryonic development
Element
m4-2-3-5-1-fertility-and-early-embryonic-development

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215

214

213

212

211

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224

223

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221

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Page 4-39

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Number
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4.2.3.5.2.3
Study Report 3

4.2.3.5.2.2
Study Report 2
m4-2-3-5-2-embryo-fetal-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-2.pdf

4.2.3.5.2.1
Study Report 1
m4-2-3-5-2-embryo-fetal-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-1.pdf

4.2.3.5.2
Embryo-fetal development
m4-2-3-5-2-embryo-fetal-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev

4.2.3.5.1.3
Study Report 3
m4-2-3-5-1-fertility-and-early-embryonic-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev/study-report-3.pdf

4.2.3.5.1.2
Study Report 2
m4-2-3-5-1-fertility-and-early-embryonic-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev/study-report-2.pdf

4.2.3.5.1.1
Study Report 1
m4-2-3-5-1-fertility-and-early-embryonic-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev/study-report-1.pdf

m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev

231

230

229

228

227

226

225

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Comment
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Title
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Comment
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Title
Element
File
Comment
Number
Title

4.2.3.5.4.2
Study Report 2

4.2.3.5.4.1
Study Report 1
m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-1.pdf

4.2.3.5.4
Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv

4.2.3.5.3.3
Study Report 3
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-3.pdf

4.2.3.5.3.2
Study Report 2
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-2.pdf

4.2.3.5.3.1
Study Report 1
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-1.pdf

4.2.3.5.3
Prenatal and postnatal development, including maternal function
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev

m4-2-3-5-2-embryo-fetal-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-3.pdf

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237

236

235

234

233

232

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Comment
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Title
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Comment
Number
Title
Element
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Comment
Number
Title

4.2.3.7.1
Antigenicity

4.2.3.7
Other Toxicity Studies (if available)
m4-2-3-7-other-toxicity-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud

4.2.3.6.3
Study Report 3
m4-2-3-6-local-tolerance
m4/42-stud-rep/423-tox/4236-loc-tol/study-report-3.pdf

4.2.3.6.2
Study Report 2
m4-2-3-6-local-tolerance
m4/42-stud-rep/423-tox/4236-loc-tol/study-report-2.pdf

4.2.3.6.1
Study Report 1
m4-2-3-6-local-tolerance
m4/42-stud-rep/423-tox/4236-loc-tol/study-report-1.pdf

4.2.3.6
Local Tolerance
m4-2-3-6-local-tolerance
m4/42-stud-rep/423-tox/4236-loc-tol

4.2.3.5.4.3
Study Report 3
m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-3.pdf

m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-2.pdf

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244

243

242

241

240

239

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Comment
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4.2.3.7.2.3

4.2.3.7.2.2
Study Report 2
m4-2-3-7-2-immunotoxicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-2.pdf

4.2.3.7.2.1
Study Report 1
m4-2-3-7-2-immunotoxicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-1.pdf

4.2.3.7.2
Immunotoxicity
m4-2-3-7-2-immunotoxicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox

4.2.3.7.1.3
Study Report 3
m4-2-3-7-1-antigenicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-3.pdf

4.2.3.7.1.2
Study Report 2
m4-2-3-7-1-antigenicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-2.pdf

4.2.3.7.1.1
Study Report 1
m4-2-3-7-1-antigenicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-1.pdf

m4-2-3-7-1-antigenicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen

252

251

250

249

248

247

246

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4.2.3.7.4.2

4.2.3.7.4.1
Study Report 1
m4-2-3-7-4-dependence
m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-1.pdf

4.2.3.7.4
Dependence
m4-2-3-7-4-dependence
m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep

4.2.3.7.3.3
Study Report 3
m4-2-3-7-3-mechanistic-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-3.pdf

4.2.3.7.3.2
Study Report 2
m4-2-3-7-3-mechanistic-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-2.pdf

4.2.3.7.3.1
Study Report 1
m4-2-3-7-3-mechanistic-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-1.pdf

4.2.3.7.3
Mechanistic studies (if not included elsewhere)
m4-2-3-7-3-mechanistic-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud

Study Report 3
m4-2-3-7-2-immunotoxicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-3.pdf

258

257

256

255

254

253

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Comment

4.2.3.7.6
Impurities
m4-2-3-7-6-impurities
m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp

4.2.3.7.5.3
Study Report 3
m4-2-3-7-5-metabolites
m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-3.pdf

4.2.3.7.5.2
Study Report 2
m4-2-3-7-5-metabolites
m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-2.pdf

4.2.3.7.5.1
Study Report 1
m4-2-3-7-5-metabolites
m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-1.pdf

4.2.3.7.5
Metabolites
m4-2-3-7-5-metabolites
m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab

4.2.3.7.4.3
Study Report 3
m4-2-3-7-4-dependence
m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-3.pdf

Study Report 2
m4-2-3-7-4-dependence
m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-2.pdf

265

264

263

262

261

260

259

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Comment
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Comment
Number
Title
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File
Comment
Number
Title
Element
File

4.2.3.7.7.3
Study Report 3
m4-2-3-7-7-other
m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-3.pdf

4.2.3.7.7.2
Study Report 2
m4-2-3-7-7-other
m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-2.pdf

m4-2-3-7-7-other
m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-1.pdf

4.2.3.7.7.1
Study Report 1

4.2.3.7.7
Other
m4-2-3-7-7-other
m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other

4.2.3.7.6.3
Study Report 3
m4-2-3-7-6-impurities
m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-3.pdf

4.2.3.7.6.2
Study Report 2
m4-2-3-7-6-impurities
m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-2.pdf

4.2.3.7.6.1
Study Report 1
m4-2-3-7-6-impurities
m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-1.pdf

269

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267

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Comment

4.3.3
Reference 3
m4-3-literature-references
m4/43-lit-ref/reference-3.pdf

4.3.2
Reference 2
m4-3-literature-references
m4/43-lit-ref/reference-2.pdf

4.3
Literature References
m4-3-literature-references
m4/43-lit-ref
Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference).
4.3.1
Reference 1
m4-3-literature-references
m4/43-lit-ref/reference-1.pdf

276

275

274

273

272

271

270

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Comment
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Title
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Directory

5.3.1.1.1
Study Report 1
m5-3-1-1-bioavailability-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-1

5.3.1.1
Bioavailability (BA) Study Reports
m5-3-1-1-bioavailability-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep

5.3.1
Reports of Biopharmaceutic Studies
m5-3-1-reports-of-biopharmaceutic-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud

5.3
Clinical Study Reports
m5-3-clinical-study-reports
m5/53-clin-stud-rep

5.2
Tabular Listing of all Clinical Studies
m5-2-tabular-listing-of-all-clinical-studies
m5/52-tab-list/tabular-listing.pdf

5.2
Tabular Listing of all Clinical Studies
m5-2-tabular-listing-of-all-clinical-studies
m5/52-tab-list

5
Clinical Study Reports
m5-clinical-study-reports
m5

Page 4-48

The applicants should ordinarily provide the study reports as multiple files (a synopsis, a main body 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.
Comment
It is possible to have the additional graphic file(s) inserted directly into the PDF file, thus making management of the file easier.
Alternatively, the applicant can choose to manage these graphic files independently.
This comment is applicable to all study reports in Module 5.
A directory should be created for each study and the files associated with the study report should be organized within the directory.
Number
5.3.1.1.2
Title
Study Report 2
277 Element
m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-2
Comment
Number
5.3.1.1.3
Title
Study Report 3
278 Element
m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-3
Comment
Number
5.3.1.2
Title
Comparative BA and Bioequivalence (BE) Study Reports
279 Element
m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep
Comment
Number
5.3.1.2.1
Title
Study Report 1
280 Element
m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep/study-report-1
Comment
Number
5.3.1.2.2
Title
Study Report 2
281 Element
m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep/study-report-2
Comment
282 Number
5.3.1.2.3
Title
Study Report 3

289

288

287

286

285

284

283

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5.3.1.4.2
Study Report 2

5.3.1.4.1
Study Report 1
m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met/study-report-1

5.3.1.4
Reports of Bioanalytical and Analytical Methods for Human Studies
m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met

5.3.1.3.3
Study Report 3
m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep/study-report-3

5.3.1.3.2
Study Report 2
m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep/study-report-2

5.3.1.3.1
Study Report 1
m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep/study-report-1

5.3.1.3
In vitro In vivo Correlation Study Reports
m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep

m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep/study-report-3

296

295

294

293

292

291

290

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Title

5.3.2.2
Reports of Hepatic Metabolism and Drug Interaction Studies

5.3.2.1.3
Study Report 3
m5-3-2-1-plasma-protein-binding-study-reports
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep/study-report-3

5.3.2.1.2
Study Report 2
m5-3-2-1-plasma-protein-binding-study-reports
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep/study-report-2

5.3.2.1.1
Study Report 1
m5-3-2-1-plasma-protein-binding-study-reports
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep/study-report-1

5.3.2.1
Plasma Protein Binding Study Reports
m5-3-2-1-plasma-protein-binding-study-reports
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep

5.3.2
Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat

5.3.1.4.3
Study Report 3
m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met/study-report-3

m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met/study-report-2

303

302

301

300

299

298

297

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Comment
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Title
Element
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Comment
Number
Title
Element
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Comment
Number
Title

5.3.2.3.3
Study Report 3

5.3.2.3.2
Study Report 2
m5-3-2-3-reports-of-studies-using-other-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-2

5.3.2.3.1
Study Report 1
m5-3-2-3-reports-of-studies-using-other-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-1

5.3.2.3
Reports of Studies Using Other Human Biomaterials
m5-3-2-3-reports-of-studies-using-other-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat

5.3.2.2.3
Study Report 3
m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud/study-report-3

5.3.2.2.2
Study Report 2
m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud/study-report-2

5.3.2.2.1
Study Report 1
m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud/study-report-1

m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud

310

309

308

307

306

305

304

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Element
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Comment
Number
Title
Element
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Comment
Number
Title
Element
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Comment
Number

5.3.3.2.1

5.3.3.2
Patient PK and Initial Tolerability Study Reports
m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep

5.3.3.1.3
Study Report 3
m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep/study-report-3

5.3.3.1.2
Study Report 2
m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep/study-report-2

m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep/study-report-1

5.3.3.1.1
Study Report 1

5.3.3.1
Healthy Subject PK and Initial Tolerability Study Reports
m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep

5.3.3
Reports of Human Pharmacokinetic (PK) Studies
m5-3-3-reports-of-human-pharmacokinetics-pk-studies
m5/53-clin-stud-rep/533-rep-human-pk-stud

m5-3-2-3-reports-of-studies-using-other-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-3

317

316

315

314

313

312

311

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Element
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Comment
Number
Title
Element
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Comment
Number
Title
Element
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Comment
Number

5.3.3.4

5.3.3.3.3
Study Report 3
m5-3-3-3-intrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-3

5.3.3.3.2
Study Report 2
m5-3-3-3-intrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-2

5.3.3.3.1
Study Report 1
m5-3-3-3-intrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-1

5.3.3.3
Intrinsic Factor PK Study Reports
m5-3-3-3-intrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep

5.3.3.2.3
Study Report 3
m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep/study-report-3

5.3.3.2.2
Study Report 2
m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep/study-report-2

Study Report 1
m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep/study-report-1

323

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321

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319

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Comment
Number
Title
Element
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Comment
Number
Title
Element
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Comment
Number
Title
Element
Directory
Comment

5.3.3.5.2
Study Report 2
m5-3-3-5-population-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep/study-report-2

5.3.3.5.1
Study Report 1
m5-3-3-5-population-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep/study-report-1

5.3.3.5
Population PK Study Reports
m5-3-3-5-population-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep

5.3.3.4.3
Study Report 3
m5-3-3-4-extrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep/study-report-3

5.3.3.4.2
Study Report 2
m5-3-3-4-extrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep/study-report-2

5.3.3.4.1
Study Report 1
m5-3-3-4-extrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep/study-report-1

Extrinsic Factor PK Study Reports


m5-3-3-4-extrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep

330

329

328

327

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325

324

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Comment
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Element
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Comment
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Title
Element
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Comment
Number
Title
Element
Directory

5.3.4.2
Patient PD and PK/PD Study Reports
m5-3-4-2-patient-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep

5.3.4.1.3
Study Report 3
m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep/study-report-3

5.3.4.1.2
Study Report 2
m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep/study-report-2

5.3.4.1.1
Study Report 1
m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep/study-report-1

5.3.4.1
Healthy Subject PD and PK/PD Study Reports
m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep

5.3.4
Reports of Human Pharmacodynamic (PD) Studies
m5-3-4-reports-of-human-pharmacodynamics-pd-studies
m5/53-clin-stud-rep/534-rep-human-pd-stud

5.3.3.5.3
Study Report 3
m5-3-3-5-population-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep/study-report-3

5.3.5
Reports of Efficacy and Safety Studies
m5-3-5-reports-of-efficacy-and-safety-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud

5.3.4.2.3
Study Report 3
m5-3-4-2-patient-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep/study-report-3

5.3.4.2.2
Study Report 2
m5-3-4-2-patient-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep/study-report-2

5.3.4.2.1
Study Report 1
m5-3-4-2-patient-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep/study-report-1

Page 4-56

5.3.5
Reports of Efficacy and Safety Studies - Indication Name
m5-3-5-reports-of-efficacy-and-safety-studies
335
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1
The folder name should always include the indication being claimed, for example, 'asthma' (abbreviated if appropriate). Where there is
Comment
more than one indication (e.g., asthma and migraine), then the first indication has a folder 'asthma' and the second 'migraine'.
Number
5.3.5.1
Title
Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
336 Element
m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr
Comment
337 Number
5.3.5.1.1
Title
Study Report 1
Element
m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication

334

333

332

331

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344

343

342

341

340

339

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5.3.5.3
Reports of Analyses of Data from More than One Study
m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study

5.3.5.2.3
Study Report 3
m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr/study-report-3

5.3.5.2.2
Study Report 2
m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr/study-report-2

5.3.5.2.1
Study Report 1
m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr/study-report-1

5.3.5.2
Study Reports of Uncontrolled Clinical Studies
m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr

5.3.5.1.3
Study Report 3
m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-3

5.3.5.1.2
Study Report 2
m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-2

m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-1

351

350

349

348

347

346

345

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Title
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Comment
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Title

5.3.5.4.3
Study Report 3

m5-3-5-4-other-study-reports
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep/study-report-2

5.3.5.4.2
Study Report 2

5.3.5.4.1
Study Report 1
m5-3-5-4-other-study-reports
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep/study-report-1

5.3.5.4
Other Study Reports
m5-3-5-4-other-study-reports
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep

5.3.5.3.3
Study Report 3
m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud/study-report-3

5.3.5.3.2
Study Report 2
m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud/study-report-2

5.3.5.3.1
Study Report 1
m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud/study-report-1

m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud

5.3.7.1
Study 1
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-1

5.3.7
Case Report Forms and Individual Patient Listings
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl

5.3.6
Reports of Postmarketing Experience
m5-3-6-reports-of-postmarketing-experience
m5/53-clin-stud-rep/536-postmark-exp

m5-3-5-4-other-study-reports
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep/study-report-3

Page 4-59

5.3.7.1.1
Document/Dataset 1
m5-3-7-case-report-forms-and-individual-patient-listings
355
m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-1.pdf
The filename and extension should include the description of the file and appropriate file extension according to Appendix 2. Reference
Comment
should be made to regional guidance for the acceptability of submission of datasets
Number
5.3.7.1.2
Title
Document/Dataset 2
356 Element
m5-3-7-case-report-forms-and-individual-patient-listings
File
m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-2.pdft
Comment
Number
5.3.7.1.3
Title
Document/Dataset 3
357 Element
m5-3-7-case-report-forms-and-individual-patient-listings
File
m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-3.pdf
Comment

354

353

352

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364

363

362

361

360

359

358

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Directory
Comment
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File
Comment
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Title
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File

5.3.7.3.2
Document/Dataset 2
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-2.pdf

5.3.7.3
Study 3
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-3
define element
5.3.7.3.1
Document/Dataset 1
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-1.pdf

5.3.7.2.3
Document/Dataset 3
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-3.pdf

5.3.7.2.2
Document/Dataset 2
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-2.pdf

5.3.7.2
Study 2
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-2
define element
5.3.7.2.1
Document/Dataset 1
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-1.pdf

369

368

367

366

365

Page 4-61

Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment

5.4.3
Reference 3
m5-4-literature-references
m5/54-lit-ref/reference-3.pdf

5.4.2
Reference 2
m5-4-literature-references
m5/54-lit-ref/reference-2.pdf

5.4
Literature References
m5-4-literature-references
m5/54-lit-ref
Copies of literature references should ordinarily be submitted as individual files (i.e,. one for each reference).
5.4.1
Reference 1
m5-4-literature-references
m5/54-lit-ref/reference-1.pdf

5.3.7.3.3
Document/Dataset 3
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-3.pdf

Page 4-62

Comment
Number
Title
374 Element
File
Comment
Number
Title
375 Element
File
Comment
376 Number
Title
Element

373

372

371

370

Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File

util/dtd/us-regional-1-0.dtd
DTD for the US specific documentation

util/dtd/jp-regional-1-0.dtd
DTD for the Japan specific documentation

DTD for the EU specific documentation

util/dtd/eu-regional-1-0.dtd

util/dtd/ich-ectd-3-2.dtd
DTD for the instance the version used to create the eCTD submission must be included

util/dtd
DTDs it is not necessary to include regional DTDs other than the one for the region to which the application is being made

util
utilities

util/style/ectd-1-0.xsl

util/style
Directory for style sheets default (ICH) and applicant specific stylesheets

util/dtd/xx-regional-1-0.dtd
DTD for the xx specific documentation, where xx is a two character country code from ISO-3166-1

Page 4-63

Comment The specific version of the eCTD stylesheet used by the applicant as a reference during the creation of the submission should be included.

File

378 Element

Title

File
Comment
Number
Title
377 Element
Directory
Comment
Number

Appendix 5: Region Specific Information Including Transmission and


Receipt
Introduction
This section describes region specific information for content that is not explicitly included in the Common
Technical Document and logistical details appropriate for the transmission and receipt of submissions using
the electronic Common Technical Document.

Region Specific Information: Module 1


This module contains administrative information that is unique for each region. There will be local
requirements for both the content and electronic component of module 1. The eCTD backbone was
developed to allow the transfer of the regional information included in a regulatory dossier.
Regional guidance will provide the specific instructions on how to provide the administrative forms and
detailed prescribing information. Please refer to this information and appendix 6 when preparing module 1.
Module 1 includes all administrative documents (e.g., forms and certifications) and labeling, including the
documents described in regional guidance.
Not all regionally specific documents are included in module 1. Technical reports required for a specific
region should be placed in modules 2 to 5. These reports should be included in the module most appropriate
for the content of the information provided.
Each region provides specific guidance on the format and content of the regional requirements of each
module. Table 5-1 provides contact information for each region.
Table 5-1

Region
European Union
Food And Drug Administration,
USA
Ministry of Health, Labour and
Welfare, Japan
Health Canada

Internet Address
http://www.emea.eu.int
http://www.fda.gov/cber
http://www.fda.gov/cder

Electronic Mail Contact


esubmission@emea.eu.int
Esubprep@cber.fda.gov
esub@cder.fda.gov

http://www.mhlw.go.jp
http://www.nihs.go.jp
http://www.hc-sc.gc.ca/hpbdgps/therapeut

e-submission@nihs.go.jp
mike_ward@hc-sc.gc.ca

Submission Addresses
Submissions should be sent directly to the appropriate regulatory authority. Information needed to send
physical media to each regulatory authority is found at the reference location in Table 5-2.
Table 5-2
Regulatory Authority
EMEA, European Union
or national agencies
Ministry of Health, Labour and Welfare, Japan
Food and Drug Administration, United States of
America
Health Canada, Health Protection Branch, Canada

Page 5-1

Reference location
http://www.eudra.org/
http://heads.medagencies.org
http://www.mhlw.go.jp
http://www.nihs.go.jp
http://www.fda.gov/
http://www.hc-sc.gc.ca/hpb-dgps/therapeut

Media
Refer to the M2 recommendations on the ICH Website for a list of media types accepted by all ICH
regions.

Cover Letter
Applicants should provide a cover letter as a PDF file (cover.pdf). A paper cover letter should also be
included with non-electronic portions of the submission (such as forms with signatures or seals, and
certifications). The cover letter should include:

A description of the submission including appropriate regulatory information.


A listing of the sections of the submission filed as paper, electronic, or both paper and electronic.
A description of the electronic submission including type and number of electronic media,
approximate size of the submission, and if appropriate, characteristics concerning the media (e.g.,
format used for DLT tapes) based on regional guidance.
A statement that the submission is virus free with a description of the software used to check the
files for viruses.
The printed contents of the index-md5.txt file as an appendix.
The regulatory and information technology points of contact for the submission.

Preparing the Media


CD-ROMs should be packaged carefully to ensure that they arrive in a usable condition. Particularly
vulnerable are diskettes and CD-ROM jewel cases shipped in envelopes without bubble-type protective
material or stiff backing. A jiffy-type bag alone does not provide adequate protection for shipping
electronic media.

Transport
Secure data exchange over the Internet is the recommended means for transporting submissions. However,
until the regulatory authorities can develop secure electronic gateways, submissions should continue to be
physically transported by courier or registered mail.

Security
An MD5 checksum should be included for each physical file in the eCTD. The checksum allows the
recipient to verify integrity of the physical files in the submission. The XML eCTD DTD provides the
location of the files and a tag name contains the checksums.
A checksum of the XML eCTD instance should also be included. Applicants should name this checksum
file index-md5.txt and include it as a file in the same directory as the XML eCTD instance. Applicants
should print the contents of the index-md5.txt file and include the paper copy with the paper cover letter for
the submission.
An applicant can provide the eCTD as an encrypted file in accordance with the ICH M2 Recommendation
4.1, if the regulatory body has implemented it. This solution allows the eCTD to be encrypted and
transferred over the Internet (if Internet receipt is implemented regionally) or to be encrypted on one of the
approved physical media standards. The purpose of encryption is to protect the privacy of the confidential
information and to ensure it is only available to the authorized receiver. Encryption is always appropriate
when the eCTD is sent via the Internet.
Encryption is not considered necessary if the information is sent using a physical media, although
encryption is an option. The applicant should assume all liability for the media until it is delivered to the
regulatory authority.

Page 5-2

Applicants should not include any file level security settings or password protection for individual files in
the eCTD. Applicants should allow printing, changes to the document, selecting text and graphics, and
adding or changing notes and form fields. Internal security and access control processes in the regulatory
authority should maintain the integrity of the submitted files.

Receipt
Upon arrival at the regulatory authority, the submission is archived according to local regulations. A readonly copy of the submission is then made available to the review community in the regulatory authority.
This is typically done by placing the copy on a network server.

Acknowledgment
Each regulatory authority should acknowledge the receipt of the eCTD submission according to the policy
and procedure of the individual regulatory authority. Applicants should use the address in Table 5-1 to find
guidance regarding acknowledgments.

Page 5-3

Appendix 6: The eCTD XML Submission


Background
Many factors have influenced the design of the eCTD. Factors that have had a significant impact on the
design are listed below:
The submissions should accommodate full regulatory dossiers, supplements, amendments, and
variations.
The submissions should be able to accommodate regional requirements that are represented in
regional guidance documents, regulations, and statutes.
The technology should be extensible so that as technology changes, the new electronic solutions
can be accommodated.
The eCTD is designed around the concept of a backbone. The backbone is similar to a container that holds
the files that are part of the submission. The backbone is based on an XML Document Type Definition
(DTD). There is a close relationship between the logical documents defined in the CTD and entities in the
backbone. The backbone will provide the navigation links to the various files and information that make
up the submission.
The file that is produced based on the XML eCTD DTD is the eCTD XML instance or XML backbone.
The XML backbone allows more than one entry or link to point to the same physical file. This should be
done with caution since managing the life cycle of that file can be more difficult for the regulatory
authority if there is more than one pointer to the file.

File Names and Directory Structure


Recipients of the eCTD should be able to directly navigate through the submission at the folder and file
level (i.e., without benefit of a customized end user application.) The structure of the eCTD and
instructions for how to create folder names facilitate this type of navigation.
In order to preserve the navigational linkages that can be present in the documents contained in the eCTD,
the directory structure should be preserved by the agencies. The navigational links should be relative links
within a module.
Specific folder and file names have been defined in appendix 4. The top level of the directory structure
will vary by region. The identification of the top-level folder uniquely identifies the submission in a
region. The submission identification should be used as the folder name in the top-level directory. For
example, if the submission number were CTD 123456, the root directory would be named ctd-123456.
The original submission and subsequent amendments and variations should use the same top-level folder
name. Submissions should be differentiated by a subfolder named according to the sequence number of the
submission in that region. Table 6-1 and Figure 6-1 illustrate this naming convention.
Table 6-1
Submission number
ctd-123456
ctd-123456

Sequence number
0000
0001

ctd-123456

0002

ctd-123456

nnnn

Page 6-1

Type of submission
Original Submission
First amendment, supplement or
variation
Second amendment, supplement
or variation
Nth amendment, supplement or
variation

Figure 6-1

You should submit the XML backbone as a single file named index.xml, which should be placed in the
submission sequence number folder for that submission. In the example shown in Figure 6-1, there should
be an index.xml file in folder 0000, folder 0001 and folder 0002. The MD5 checksum file, indexmd5.txt, should be in each folder with the corresponding index.xml file. The DTD for index.xml should be
in the util folder for each submission.
The regional administrative XML backbone file, if supplied, should be in the region specific module 1
folder for each submission. The DTD for the regional XML backbone file should be in the util folder for
each submission.
Table 6-2 presents the file locations for the example in Figure 6-1.
Table 6-2
Submission Folder
ctd-123456/0000
ctd-123456/0000/m1/us
ctd-123456/0000/util
ctd-123456/0001
ctd-123456/0001/m1/us
ctd-123456/0001/util/dtd
ctd-123456/0002
ctd-123456/0002/m1/us
ctd-123456/0002/util/dtd

Files
index.xml
index-md5.txt
us-regional.xml
ich-ectd-3-2.dtd
us-regional-1-0.dtd
index.xml
index-md5.txt
us-regional.xml
ich-ectd-3-2.dtd
us-regional-1-0.dtd
index.xml
index-md5.txt
us-regional.xml
ich-ectd-3-2.dtd
us-regional-1-0.dtd

Lifecycle Management
It is important for the recipients of an eCTD to be able to establish the location of the submission in the
lifecycle of a product.
The eCTD is capable of containing initial submissions, supplements, amendments, and variations. There
are no uniform definitions for these terms in the three regions, but amendments and supplements are terms
used in the United States. Variations apply in Europe. The variations, supplements, and amendments are
used to provide additional information to an original regulatory dossier. For example, if a new
manufacturer for the drug substance were being proposed, this would result in submission of an amendment
or supplement to the FDA and a variation to Europe. When regulatory authorities request additional
information, the information is also provided as a variation, supplement, or amendment to the original

Page 6-2

submission. Therefore, the regulatory agencies should have a way to manage the lifecycle of the
submission. This function should be provided by each regulatory authority in the form of guidance that can
include regional DTDs and specifications. The relevant regional DTD should be referenced in the eCTD
DTD by the applicant.
The eCTD DTD provides some facilities for lifecycle management at the file level but does not fully
support the life cycle at the submission level. When revisions are sent to a regulatory authority, the new
file should be submitted as a leaf element associated with the same tag name as the file being amended or
deleted. The modified-file attribute of the leaf element should contain the leaf ID of the file being
amended, replaced, or deleted. This will allow the regulatory authority to accurately locate the original file
and update the original files status. A detailed description of modified-file is provided in the next section.

Operation Attribute
The operation attribute is a key to managing each individual file in a submission. The applicant uses the
operation attribute to tell the regulatory authority how the applicant intends the files in the submission to be
used. The operation attribute describes the relation between files in subsequent submissions during the life
cycle of a medicinal product. In the very first submission all the files will be new. In the second, third, and
subsequent submissions, all the newly submitted files can have different operation attributes due to having
or not having a relation with previously submitted files. Table 6-2 describes the meaning of each allowed
value of the operation attribute.
Table 6-3 Understanding the Operation Attribute

Operation
attribute
value
New
Append

Replace
Delete

Meaning
The file has no relationship with files submitted
previously.
This means there is an existing file to which this new
file should be associated. (e.g., providing missing or
new information to that file). It is recommended that
append not be used to associate two files in the same
submission (e.g., splitting a file due to size restrictions).
This means there is an existing file that this new file
replaces.
There is no new file submitted in this case. Instead, the
leaf has the operation of delete and the modifiedfile attribute identifies the file in a previous submission
that is to be considered no longer relevant to the review.

What the reviewer might see


when using the Agency review
software
This file
Previous file
Current
Current

Current Appended

Current

Replaced
No longer
relevant to the
review

The purpose of the modified-file attribute is to provide the location of a document that is being modified
(i.e. replaced, appended or deleted) by the leaf element. The modified-file attribute should have a value
when the operation attribute has a value of append, replace or delete. The modified-file attribute points to
the index.xml file and the leaf ID of the file being altered.
An example of a modified file attribute value is provided below:
modified-file="../0001/index.xml#a1234567"
This would provide the information needed to locate the file with the leaf element ID assigned as
"a1234567" and provided in the sequence folder numbered "0001".

Page 6-3

If a modified-file attribute is presented with no value (i.e. no characters or spaces between the quotation
marks, modified-file="") it will be the same as not including the attribute in the leaf element.
The following case examples show the use of each of the operation attribute values. These examples do not
cover all possible situations. Consult the appropriate regulatory authority if you have specific questions
about the use of the operation attribute. When actually populating the XML instance, use the leaf ID to
refer to files.
Case 1 The first submission of a dossier.
Submission
sequence #
0000

File name
0000\\structure.pdf

Table 6-4
Operation
File Being
Modified
New

Sample logical display


in a review tool
structure.pdf (current)

Case 2 Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is a
subsequent amendment or variation in which the applicant intends to completely replace the structure.pdf
file in submission 0000. The intent is to keep the original structure.pdf for historical purposes but to
consider only the contents of the 0001\\structure.pdf as relevant to the review. These two submissions
could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf, and this file is the current
version of this file.
- Submission 0001, which is submitted at a later time, is the submission of the file
structure.pdf, which is now current and replaces the file structure.pdf in submission 0000.
Table 6-5
Submission
File name
Operation File Being Modified Sample logical display
sequence #
in a review tool
0000
0000\\structure.pdf New
structure.pdf (current)
0001
0001\\structure.pdf Replace
0000\\structure.pdf structure.pdf (replaced)
structure.pdf (current)
Case 3 Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is an
amendment or variation where the applicant intends to add new information to the original structure.pdf
file, which was submitted in submission 0000. The intent is to have the reviewer consider the contents of
both files relevant to the submission. These two submissions could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf, and this file is the current
version of this file.
- Submission 0001, submitted at a later time, is the submission of the file structure.pdf, which
is the current file but contains information that should be appended to file structure.pdf in
submission 0000. Both files should be considered relevant to the review of the dossier.

Submission
sequence #

File name

Table 6-6
Operation Modified file

0000
0001

0000\\structure.pdf
0001\\structure.pdf

New
Append

0000\...\structure.pdf

Sample logical
display in a review
tool
structure.pdf (current)
structure.pdf (current appended)
structure.pdf (current)

Case 4 Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is an
amendment or variation where the applicant intends to delete a file in the previous submission. The intent

Page 6-4

is to have the reviewer disregard the contents of the original file, possibly because it should not have been
submitted with the original dossier. These two submissions could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf and this file is the current
version of this file.
- Submission 0001, submitted at a later time, requests that the file structure.pdf in submission
0000 be deleted and no longer considered relevant to the review of the dossier.
Submission
sequence #
0000
0001

File name
0000\...\structure.pdf

Table 6-7
Operation File Being
Modified
New
Delete
0000\...\structure.pdf

Sample logical display in


a review tool
structure.pdf (current)
structure.pdf (no longer
relevant to the review)

DTD Content Model


The content model of the eCTD is derived from the organization of the Common Technical Document.
The graphic representation of a portion of the content model is shown below. The content model is
hierarchical starting at the ectd and going down to a specific item to be included in the submission. This
example shows how the section of the CTD containing summaries is structured.

Page 6-5

Once the appropriate tag has been selected, use the <leaf> element and attributes to specify a file in the
submission. See Instructions for preparing the eCTD in this appendix for details.

Page 6-6

eCTD Element/Attribute Instructions


The eCTD consists of 5 primary modules:

m1-administrative-information-and-prescribing-information

m2-common-technical-document-summaries

m3-quality

m4-nonclinical-study-reports

m5-clinical-study-reports

Each of the 5 modules is divided into sub elements, each with a distinct <tag> that represents a CTD table
of contents location. The steps should be completed as shown in the following example, where all files are
submitted for modules 1 through 5:
1.
2.
3.
4.
5.

You should select a tag element that best corresponds to the CTD table of contents location for a
document or file being submitted. For example, select the tag <m2-4-nonclinical-overview> to submit
the nonclinical overview document.
You should create a child <leaf> element underneath the <m2-4-nonclinical-overview> tag.
You should provide the relative location and file name of the actual file containing the nonclinical
overview in the xlink:href attribute for the <leaf> element.
You should provide a descriptive title for the file that contains the nonclinical overview in the <title>
element of the <leaf>.
You should provide information for the appropriate attributes of the <leaf> element as described in
Table 6-8.

The table 6-8 describes each of these elements and attributes in further detail. In the current review
environment, the following leaf attributes are the most useful to the end user:

ID
xml:lang
checksum
checksum-type
modified-file
operation

Page 6-7

application-version
xlink:href

Table 6-8
Element
Attribute
Any table of
contents tag
such as <m24nonclinicaloverview>

<leaf>

Page 6-8

Description/Instructions
Example
A table of contents tag represents a
grouping of one or more files related
to a specific section of the Common
Technical Document.
One or more child <leaf> elements
can be declared for a parent table of
contents tag.
It is possible to extend a table of
contents tag by providing a <nodeextension> element. This can be done
at the lowest level of the defined table
of contents tags but should be done
only when absolutely necessary. See
the section Instructions for extending
eCTD tag elements in this appendix.
ID
A unique identifier for this location in id403 (note: At this level, ID is optional
the XML instance.
and may provide for navigation within
the index.
xml:lang
The primary language used by the
En
files in this entire section of the
submission. Use ISO-639 standard
language abbreviations
A leaf corresponds to a file.
One or more child leaf elements can
be submitted for a parent table of
contents tag.
application- The version of the software
PDF 1.3
version
application that was used to create this
file.
font-library Commercial name of fonts/font set
used to create the document.
ID
Unique identifier for this file in the
id050520
XML instance. Leaf ID must start
with a character.
checksum
The checksum value for the file being e854d3002c02a61fe5cbe926fd97b001
submitted.
checksum- The checksum algorithm used.
MD5
type
modifiedThe purpose of the modified-file
modifiedfile
attribute is to provide the location of a file="../0001/index.xml#a1234567"
document that is being modified (i.e.
replaced, appended or deleted) by the
leaf element. The modified-file
attribute should have a value when the
operation attribute has a value of
append, replace or delete. The
modified-file attribute points to the
index.xml file and the leaf ID of the
file being altered.

Element

<title>

Attribute
operation

Description/Instructions
Indicates the operation to be
performed on the modified-file.
You should select one of the
following valid values:
new
replace
append
delete
See the section Operation Attribute in
this appendix for details on the
meaning of these values.
version
The file submitters internal version
number or version identification for
the report.
xlink:actuate Not Currently Used
xlink:href
Provide the pointer to the actual file.
Use the relative path to the file and
the file name.
xlink:role
Not Currently Used
xlink:show Not Currently Used.
xlink:type Fixed value of simple.
keywords
Not Currently Used
This element is associated with a
leaf and provides a description of
the file being submitted.
ID
Unique identifier for this location in
the XML instance. Leaf ID must start
with a character.

Example
New

V23.5

0000/m2/27-clin-sum/literaturereferences.pdf

simple
study report 1234
a1234567

Instructions for a Simple New Submission7


The following XML fragment demonstrates the submission of a clinical overview of efficacy as a single
PDF document.
<?xml version = "1.0" encoding = "UTF-8"?>
<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-2.dtd">
<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<m2-common-technical-document-summaries>
<m2-5-clinical-overview xml:lang = "en">
<leaf ID="s123456" operation = "new" xlink:type = "simple" checksum-type=md5
checksum =
"e854d3002c02a61fe5cbe926fd973401"
xlink:href = "m2/25-clin-over/clinical-overview.pdf"
application-version = "PDF 1.3">
<title>Clinical Overview</title>
</leaf>
</m2-5-clinical-overview>
</m2-common-technical-document-summaries>
</ectd:ectd>

This submission includes the file clinical-overview.pdf in the relative directory m2/25-clin-over/ (i.e.
the one starting below the dossier number directory). The file is new and has a descriptive name of
Clinical Overview
7

Note that these XML examples are examples only and do not necessarily contain all of the elements and
attributes that you should use when preparing an eCTD submission.

Page 6-9

The regional review application should treat this as a new submission to be associated with the submission
identified in CTD module 1, which is region specific.
If this is the first submission for Dossier CTD 123456, all the files in this submission are in the ctd123456\0000 directory and below.

Instructions for an Amendment, Supplement, or Variation


In the previous example, a clinical overview was submitted. In this example, it is replaced by an updated
version.
To replace a file, add the replacement file <leaf> element under the same tag element as the original file. If
this is the second submission for Dossier CTD 123456, all the files in this submission are in the ctd123456\0001 directory and below.
<?xml version = "1.0" encoding = "UTF-8"?>
<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-2.dtd">
<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<m2-common-technical-document-summaries>
<m2-5-clinical-overview xml:lang = "en">
<leaf ID=a123457 operation = "replace"
xlink:type = "simple" checksum-type=md5 checksum =
"e854d3002c02a61fe5cbe926fd973401"
xlink:href = "m2/25-clin-over/clinical-overview.pdf"
application-version = "Acrobat 5"
modified-file = "../0000/index.xml#a123456">
<title>Clinical Overview</title>
</leaf>
</m2-5-clinical-overview>
</m2-common-technical-document-summaries>
</ectd:ectd>

Instructions for Multiple Indications


Multiple therapeutic indications use an additional attribute associated with the <m2-7-3-summary-ofclinical-efficacy> and the <m5-3-5-reports-of-efficacy-and-safety-studies> elements to allow multiple
indications to be submitted. The following table shows the use of these attributes.

Table 6-9
Element

Attribute

<m2-7-3-summary-of-clinical-efficacy>

Indication

<m5-3-5-reports-of-efficacy-and-safety-studies>

Indication

Description/Instructions

Name of the indication


Name of the indication.

Example
pain
pain

Note that the indication attribute is used by the regulatory authority to apply to all the table of contents tags
beneath the <m2-7-3-summary-of-clinical-efficacy> and <m5-3-5-reports-of-efficacy-and-safety-studies>
tags. This is an example of a section of the instance showing the submission of information about two
indications:
<?xml version = "1.0" encoding = "UTF-8"?>
<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-2.dtd">
<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<m2-common-technical-document-summaries>
<m2-7-clinical-summary>
<m2-7-3-summary-of-clinical-efficacy indication = "pain">
<leaf ID=s123456operation = "new" xlink:type = "simple"
checksum-type=md5 checksum =
"e854d3002c02a61fe5cbe926fd973401"

Page 6-10

xlink:href =
"m2/27-clin-sum/summary-clin-efficacy-pain.pdf">
<title>pain efficacy summary</title>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>
<m2-7-3-summary-of-clinical-efficacy indication = "nausea">
<leaf ID=a123457 operation = "new" xlink:type = "simple"
checksum-type=md5 checksum =
"e854d3002c02a61fe54be926fd973401"
xlink:href =
"m2/27-clin-summ/summary-clin-efficacy-nausea.pdf">
<title>nausea efficacy summary</title>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>
</m2-7-clinical-summary>
</m2-common-technical-document-summaries>
<m5-clinical-study-reports>
<m5-3-clinical-study-reports>
<m5-3-5-reports-of-efficacy-and-safety-studies indication = "pain">
<leaf ID=a123458 operation = "new" xlink:type = "simple" checksumtype=md5
checksum =
"e854d3002c02a61fe544e926fd973401"
xlink:href =
"m5/53-clin-stud-rep/535-rep-eff-safety-stud/pain/pain-sr1.pdf">
<title>pain study report 1</title>
</leaf>
</m5-3-5-reports-of-efficacy-and-safety-studies>
<m5-3-5-reports-of-efficacy-and-safety-studies indication = "nausea">
<leaf ID=a123459 operation = "new" xlink:type = "simple" checksumtype=md5 checksum =
"e854d3002c02a614e54be926fd973401"
xlink:href =
"m5/53-clin-stud-rep/535-rep-eff-safety-stud/nausea/nausea-sr15.pdf">
<title>nausea study report 15</title>
</leaf>
</m5-3-5-reports-of-efficacy-and-safety-studies>
</m5-3-clinical-study-reports>
</m5-clinical-study-reports>
</ectd:ectd>

Instructions for Multiple Drug Substances, Manufacturers, and Products


Multiple drug substances use additional attributes associated with the <m3-2-s-drug-substance> element to
allow unique combinations of the drug substance name and manufacturer to be submitted. The following
table shows the use of these attributes.

Table 6-10
Element

Attribute

Description/Instructions

Example

Name of one of the drug substances


Acetaminophen
Manufacturer Name of the manufacturer of the drug substance my supplier

<m3-2-s-drug-substance> Substance

This is an example of a section of the instance showing the submission of information about two drug
substances, one of which is supplied by two manufacturers:
<m3-2-body-of-data>
<m3-2-s-drug-substance substance = "acetaminophen" manufacturer = "my supplier">
<leaf ID=a123456 operation = "new" xlink:type = "simple" checksum-type=md5
checksum =
"e854d3002c02361fe54be926fd973401"

Page 6-11

xlink:href =
"m3/32-body-data/32s-drug-sub/acetaminophen-my-supplier/acetaminophen.pdf">
<title>acetaminophen my supplier data</title>
</leaf>
</m3-2-s-drug-substance>
<m3-2-s-drug-substance substance = "acetaminophen" manufacturer = "bulk company 2">
<leaf ID=a123457 operation = "new" xlink:type = "simple" checksum-type=md5
checksum =
"e854d3002402a61fe54be926fd973401"
xlink:href =
"m3/32-body-data/32s-drug-sub/acetaminophen-bulk-company-2/acetaminophen2.pdf">
<title>acetaminophen company 2 data</title>
</leaf>
</m3-2-s-drug-substance>
<m3-2-s-drug-substance substance = "codeine" manufacturer = "drug company 2">
<leaf ID=a123458 operation = "new" xlink:type = "simple" checksum-type=md5
checksum =
"e854d3002c02461fe54be926fd973401"
xlink:href =
"m3/32-body-data/32s-drug-sub/codeine-drug-company-2/codeine-quality-data.pdf">
<title>codeine data</title>
</leaf>
</m3-2-s-drug-substance>
</m3-2-body-of-data>

Multiple drug products use additional attributes associated with the <m3-2-p-drug-product> element to
allow unique combinations of the drug product name and dosage form to be submitted. The following table
shows the use of these attributes.

Table 6-11
Element

Attribute

Description/Instructions

<m3-2-p-drug-product> product-name Name of one of the drug products

Example
Wonder drug

Dosage form and strength of the drug product Tablet-5 mg


manufacturer Manufacturer of the drug product
Company A
dosageform

This is an example of a section of the instance showing the submission of information about two drug
products:
<m3-2-body-of-data>
<m3-2-p-drug-product product-name = wonder drug dosageform=capsule-5mg>
<leaf ID=a123456 operation = "new" xlink:type = "simple" checksum-type=md5 checksum =
"e854d3002c02a61fe5cbe226fd973401"
xlink:href =
"m3/32-body-data/32p-drug-prod/capsule-5mg/32p1-desc-comp/description-andcomposition.pdf">
<title>wonder drug capsule product information</title>
</leaf>
</m3-2-p-drug-product>
<m3-2-p-drug-product product-name = wonder drug dosageform=tablet-5mg>
<leaf ID=a123457 operation = "new" xlink:type = "simple" checksum-type=md5 checksum =
"e854d3002c02a61fe5cbe926fd973401"
xlink:href =
"m3/32-body-data/32p-drug-prod/tablet-5mg/32p1-desc-comp/description-andcomposition.pdf">
<title>wonder drug tablet product data</title>
</leaf>
</m3-2-p-drug-product>
</m3-2-body-of-data>

Page 6-12

Instructions for Extending XML eCTD DTD Elements


An applicant can extend the definition of an element by creating node extensions beneath a defined table of
contents tag. Using node extensions is discouraged and should only be done when there is no other feasible
means to submit information. The child element <node-extension> should be used for each new table of
contents node created. The <title> element value is inherited from the parent element. You should follow
the following principles when using <node-extension>:
1.
2.

You should only extend the lowest level of defined elements. For example you can extend the
<m2-3-r-regional-information> element but not the <m2-3-quality-overall-summary> element
since the latter is not the lowest element defined in the table of contents.
Do not extend the element more than one level. For example, you should not extend <nodeextension> <title>special-fda-summary</title> </node-extension> with another <node-extension>.

The following is an example of a section of the eCTD instance in which an applicant extends the <m2-3-rregional-information> to provide specific regional information as requested by a regulatory authority. The
title element associated with the <node-extension> describes the extension. Alternatively, the regional
information in this example could have been provided as a <leaf> element under the <m2-3-r-regionalinformation> element without the use of a node extension.
<m2-common-technical-document-summaries>
<m2-3-quality-overall-summary>
<m2-3-r-regional-information>
<node-extension>
<title>special-fda-summary</title>
<leaf ID=a123456 operation = "new" xlink:type = "simple" xlink:href =
"m2/23-qos/fda/fda-extra-quality-sum.pdf">
<title> FDA extra quality summary </title>
</leaf>
</node-extension>
</m2-3-r-regional-information>
</m2-3-quality-overall-summary>
</m2-common-technical-document-summaries>

To update a file that has been submitted as an extended node, you should submit the replacement file using
exactly the same element and node extension information, including the <title> element for the <nodeextension>. This makes it possible for the regulatory authority to locate the original file and update its
status.

Instructions for Submitting Sections as Paper


During the transition to fully electronic submissions of the CTD, some regions will accept that some
sections can be submitted as paper only. Please refer to regional guidance. These sections should be
identified in the XML eCTD instance by including a PDF file in the instance that describes the content and
location of the paper section. For example, the PDF file might consist of only one page with the name of
the CTD document and the physical volume number and tab identifier. The <title> element in the XML
eCTD instance could indicate that this is a paper submission.
This is an example of the instance showing the submission of a paper efficacy overview document.
<m2-common-technical-document-summaries>
<m2-5-clinical-overview xml:lang = "en">
<leaf ID=a123456 operation = "new" xlink:type = "simple" checksum-type=md5
checksum =
"e854d3002c02a61fe5cbe926fd973401" ID=ID050520
xlink:href = "m2/25-clin-over/clinical-overview.pdf"
application-version = "Acrobat 5">

Page 6-13

<title>Paper Submission </title>


</leaf>
</m2-5-clinical-overview>
</m2-common-technical-document-summaries>

Page 6-14

Appendix 7: Specification for Submission Formats


Introduction
This appendix describes the way files should be constructed for inclusion in the eCTD. This section
includes file formats that are commonly used in electronic submissions. Other formats can be used
according to guidance published in each region.

PDF
Adobe Portable Document Format (PDF) is a published format created by Adobe Systems Incorporated
(http://www.adobe.com). It is not necessary to use a product from Adobe or from any specific company to
produce PDF documents. PDF is accepted as a standard for documents defined in this specification. The
following recommendations support the creation of PDF files that agencies can review effectively. For any
specification of the Japanese version of Adobe Acrobat, or where Japanese characters will be in the file,
please refer to the regional guidance.
To ensure that PDF files can be accessed efficiently, PDF files should be no larger than 100 megabytes.
Optimize PDF files for fast web view.

Version
Agencies should be able to read all PDF files with version 4.0 or higher of the Acrobat Reader. Agencies
should not need any additional software to read and navigate the PDF files. However, review can be
facilitated through use of Adobe Acrobat since significantly more functionality is available in this product
than with Acrobat Reader.

Fonts
PDF viewing software automatically substitutes a font to display text if the font used to create the text is
unavailable on the reviewers computer. Font substitution can affect a documents appearance and
structure, and in some cases, the information conveyed by a document. Agencies cannot guarantee the
availability of any fonts except Times New Roman, Arial, and Courier and fonts supported in the Acrobat
product set itself. Therefore, all additional fonts used in the PDF files should be embedded to ensure that
those fonts would always be available to the reviewer. When embedding fonts, all characters for the font
should be embedded, not just a subset of the fonts being used in the document
Embedding fonts requires additional computer storage space. Three techniques to help limit the storage
space taken by embedding fonts include:
Limiting the number of fonts used in each document

Using only True Type or Adobe Type 1 fonts

Avoiding customized fonts

Japanese fonts (2-byte fonts) are larger than Roman fonts (1-byte fonts), therefore, the specification allows
a subset to be embedded for all Japanese fonts. The purpose of embedding fonts to is to allow the receiver
of the document to use a personal computer to display and print the document correctly without having the
same fonts installed in the computer. Therefore, it is not necessary to embed all Japanese fonts. Embedding
a subset of Japanese fonts should work satisfactorily.

Definition of Subset
A subset means to embed only those characters used in the document. Embedding a full-set means all
characters that comprise the font are embedded, even characters that are not used in the document. All
two-byte fonts such as Japanese should be embedded as a sub-set.

Notes on Embedding Japanese Fonts:

Page 7-1

The following should be considered when embedding fonts:


Advantages:
Embedding fonts allows the PDF file to be correctly displayed and printed on any receiving PC
environment.
The computer does not need the original fonts installed.
Disadvantages:
The file size increases when fonts are embedded.
When document contains many pages, this may make the document slower to print.
Many eCTD documents contain a large number of pages. Printing time in such cases becomes a
concern.
When using Japanese fonts, rules of operation should be established between the sender and receiver.
(See regional guidance)
The use of popular fonts only would allow the sender and receiver to view and print the document
correctly without embedding fonts.

Font Size
Resizing a document because the contents are too small to read is inefficient. Times New Roman, 12-point
font, the font used for this document, is adequate in size for narrative text and should be used whenever
possible. It is sometimes tempting to use fonts which are smaller than 12 point in tables and charts but this
should be avoided whenever possible. When choosing a font size for tables, a balance should be sought
between providing sufficient information on a single page to facilitate data comparisons for the reviewer
while maintaining a font size that remains legible. The corollary of this is that in using larger font size,
more tables might be necessary, which can complicate data comparisons since data might now be included
in separate tables. Generally, Times New Roman font sizes 9-10 or an equivalent size of other
recommended fonts are considered acceptable in tables but smaller font sizes should be avoided.

Use of Color Fonts


The use of a black font color is recommended. Blue can be used for hypertext links. Light colors that do
not print well on grayscale printers should be avoided. Color reproduction can be tested prior to
submission by printing sample pages from the document using a gray scale printer. The use of background
shadowing should be avoided.

Page Orientation
Pages should be properly oriented so that all portrait pages are presented in portrait and all landscape pages
are presented in landscape. To achieve this, the page orientation of landscape pages should be set to
landscape prior to saving the PDF document in final form.

Page Size and Margins


The print area for pages should fit on a sheet of A4 (210 x 297 mm) and Letter (8.5 x 11) paper. A
sufficient margin (at least 2.5 cm) on the left side of each page should be provided to avoid obscuring
information if the reviewer subsequently prints and binds the pages for temporary use. For pages in
landscape orientation (typically tables and publications), smaller margins (at least 2.0 cm at the top and 0.8
cm left and right) allow more information to be displayed legibly, on the page (see Fonts). Header and
footer information can appear within these margins but not so close to the page edge to risk being lost upon
printing.

Source of Electronic Document


PDF documents produced by scanning paper documents are usually inferior to those produced from an
electronic source document. Scanned documents saved as image files are more difficult to read and do not
allow reviewers to search or copy and paste text for editing. Scanning should be avoided where possible.

Page 7-2

Methods for Creating PDF Documents and Images


The method used for creating PDF documents should produce the best replication of a paper document. To
ensure that the paper and PDF version of the document are the same, the document should be printed from
the PDF version. Documents that are available only in paper should be scanned at resolutions that will
ensure the pages are legible both on the computer screen and when printed. At the same time, the file size
should be limited. It is recommended that scanning be undertaken at a resolution of 300 dots per inch (dpi)
to balance legibility and file size. The use of grayscale or color is discouraged because of file size. After
scanning, resampling to a lower resolution should be avoided.
When creating PDF files containing images, the images should not be downsampled. Downsampling does
not preserve all of the pixels in the original. For PDF images, one of the following lossless compression
techniques should be used:

For lossless compression of color and grayscale images, use Zip/Flate (one technique with two names).
This is specified in Internet RFC 1950 and RFC 1951 (http://info.internet.isi.edu/innotes/rfc/files/rfc1950.txt).
For lossless compression of black and white images, use the CCITT Group 4 Fax compression
technique. It is specified as CCITT recommendations T.6 (1988) - Facsimile coding schemes and
coding control functions for Group 4 facsimile apparatus.

Paper documents containing hand-written notes should be scanned at 300 dpi. Hand-written notes should
be done in black ink for clarity.
For photographs, the image should be obtained with a resolution of 600 dpi. If black and white photos are
submitted, 8-bit grayscale images should be considered. If color photos are submitted, 24-bit RGB images
should be considered. A captured image should not be subjected to non-uniform scaling (i.e., sizing).
Gels and karyotypes should be scanned directly, rather than from photographs. Scanning should be at 600
dpi and 8-bit grayscale depth.
Plotter output graphics should be scanned or captured digitally at 300 dpi.
High-pressure liquid chromatography or similar images should be scanned at 300 dpi.
Applicants should validate the quality of the renditions.

Hypertext Linking and Bookmarks


Hypertext links and bookmarks improve navigation through PDF documents. Hypertext links can be
designated by rectangles using thin lines or by blue text as appropriate.
In general, for documents with a table of contents, bookmarks for each item listed in the table of contents
should be provided including all tables, figures, publications, other references, and appendices. Bookmarks
should follow hierarchical level and order of table of contents. These bookmarks are essential for the
efficient navigation through documents. The bookmark hierarchy should be identical to the table of
contents with no additional bookmark levels beyond those present in the table of contents. Each additional
level increases the need for space to read the bookmarks. The use of no more than 4 levels in the hierarchy
is recommended.
Hypertext links throughout the document to support annotations, related sections, references, appendices,
tables, or figures that are not located on the same page are helpful and improve navigation efficiency.
Relative paths should be used when creating hypertext links to minimize the loss of hyperlink functionality
when folders are moved between disk drives. Absolute links that reference specific drives and root
directories will no longer work once the submission is loaded onto the Agencys network servers.

Page 7-3

When creating bookmarks and hyperlinks, the magnification setting Inherit Zoom should be used so that
the destination page displays at the same magnification level that the reviewer is using for the rest of the
document.

Page Numbering
Only the internal page numbers of the document are required (1-n). No additional page/volume numbers
running across documents are expected. It is easier to navigate through an electronic document if the page
numbers for the document and the PDF file are the same. To accomplish this, the first page of the
document should be numbered page 1, and all subsequent pages (including appendices and attachments)
should be numbered consecutively with Arabic numerals. Roman numerals should not be used to number
pages (e.g., title pages, tables of contents) and pages should not be left unnumbered (e.g., title page.)
Numbering in this manner keeps the Acrobat numbering in synchrony with the internal document page
numbers.
Two exceptions to this rule can occur (see details in the guidance for the modules of the CTD.
First, where a document is split because of its size (e.g., >50MB), the second or subsequent file
should be numbered consecutively to that of the first or preceding file.
Second, where several small documents with their own internal page numbering have been
combined into a single file, it is not necessary to provide additional page numbering, instead the
start of each sub document should be book marked.

Document Information Fields


Recommendations for the document information fields will be provided in the regional guidance for the
specific submission type.

Open Dialog Box


The open dialog box sets the document view when the file is opened. The initial view of the PDF files
should be set as Bookmarks and Page. If there are no bookmarks, the initial view as Page only should be
set. The Magnification and Page Layout should be set as default.

Security
No security settings or password protection for PDF files should be included. Security fields should be set
to allow printing, changes to the document, selecting text and graphics, and adding or changing notes and
form fields.

Indexing PDF Documents


There are no current plans in the ICH regions to use full text indexes.

Use of Acrobat Plug-Ins


It is appropriate to use plug-ins to assist in the creation of a submission. However, the review of the
submission should not require the use of any plug ins in addition to those provided with Adobe Acrobat
because agencies should not be required to archive additional plug-in functionality.

XML Files
A working group at the World Wide Web Consortium (W3C) developed XML. It is a nonproprietary
language developed to improve on previous markup languages including standard generalized markup
language (SGML) and hypertext markup language (HTML).
Information in an XML file is divided into specific pieces. These pieces are called objects or element types.
The element type identifies the piece of information. For example, the name of the company submitting a
registration application in eCTD format for review is identified with the element type <applicant>. All
element type names are bracketed using the special characters <>. Inside the XML document, the element

Page 7-4

type name is placed just prior to the piece of information and after the information. This is called tagging.
So, in the XML file, the applicant could be tagged as follows <applicant>Worldwide Pharmaceuticals
Inc.</applicant>. The / prior to the element type denotes that this is the end of the information about the
applicant.
By using a hierarchical structure, XML allows you to relate two or more elements. This is accomplished by
nesting one element within another.
Additional information about the element type is provided by attributes. Attributes are placed within the
element types and are surrounded by quotation marks ( .) For example, if you wanted to show that the
applicant name is presented in the English language, you could add this piece of information as an attribute.
This could be represented in the XML file as <applicant XML:LANG=EN> Worldwide Pharmaceuticals
Inc.</applicant>.
XML files are read by a parser found in Internet browsers. Stylesheets provide the browser with the
information to create tables, fonts, and colors for display.
The specific names of the element types and attributes as well as the valid syntax, structure and format for
defining the XML elements are included in a file called document type definition (DTD). If the XML
document does not follow the DTD, then the file will not be able to be used properly.
The top three lines of the XML file should include the XML version, the stylesheet type and address, and
the DTD name and address.
Additional information about the XML standard can be found at the W3C Web site at http://www.w3c.org.

SVG Files
SVG is a language for describing two-dimensional graphics in XML. SVG allows for three types of
graphic objects: vector graphic shapes (e.g., paths consisting of straight lines and curves), images, and
text. Graphical objects can be grouped, styled, transformed and composited into previously rendered
objects. Text can be in any XML namespace suitable to the application, which enhances searchability
and accessibility of the SVG graphics. The feature set includes nested transformations, clipping paths,
alpha masks, filter effects, template objects, and extensibility.
SVG drawings can be dynamic and interactive. The Document Object Model (DOM) for SVG, which
includes the full XML DOM, allows for straightforward and efficient vector graphics animation via
scripting. A rich set of event handlers such as onmouseover and onclick can be assigned to any SVG
graphical object. Because of its compatibility and leveraging of other Web standards, features like
scripting can be done on SVG elements and other XML elements from different namespaces
simultaneously within the same Web page. 8
The specific use of SVG in a submission should be discussed with the regulatory authority.

This description of SVG is from w3c Web page http://www.w3c.org/graphics/svg

Page 7-5

Appendix 8: XML eCTD DTD


<?xml version='1.0' encoding='UTF-8' ?>
<!-- Changes prior to Version 1.00 captured in file
"Historical Changes.txt
ICH eCTD DTD
Version 1.0 - March 6, 2002
Version 3.0 - Sept 11, 2002
Version 3.0 - Oct 1, 2002
Version 3.0 - Oct 8, 2002
Version 3.1 - Nov 11, 2003
Version 3.2 - Nov 21, 2003
Changes in version 3.1
- ID was changed to REQUIRED in the following four locations:
<!ENTITY % att " ID
ID #REQUIRED
xml:lang CDATA #IMPLIED">
<!ELEMENT leaf (title, link-text?)>
<!ATTLIST leaf
ID ID #REQUIRED <attlist continues>
<!ELEMENT xref EMPTY>
<!ATTLIST xref
ID ID #REQUIRED <attlist continues>
<!ELEMENT node-extension (title, (leaf | node-extension)+)>
<!ATTLIST node-extension
ID ID #REQUIRED
xml:lang CDATA #IMPLIED>
Changes in version 3.2
- Indication attribute was changed to REQUIRED in the following two locations:
<!ATTLIST m2-7-3-summary-of-clinical-efficacy
%att;
indication CDATA #REQUIRED
<!ATTLIST m5-3-5-reports-of-efficacy-and-safety-studies
%att;
indication CDATA #REQUIRED
-

Since ID is only needed for files referenced in a LEAF, changed ID back to IMPLIED for:
<!ENTITY % att " ID
ID #REQUIRED
xml:lang CDATA #IMPLIED">
<!ELEMENT node-extension (title, (leaf | node-extension)+)>
<!ATTLIST node-extension
ID ID #REQUIRED
xml:lang CDATA #IMPLIED>

Page 8-1

End of changes
-->
<!ENTITY % att " ID
ID #IMPLIED
xml:lang CDATA #IMPLIED">
<!-- ============================================================= -->
<!-- Top-level element -->
<!-- ============================================================= -->
<!ELEMENT ectd:ectd (m1-administrative-information-and-prescribing-information? , m2-commontechnical-document-summaries? , m3-quality? , m4-nonclinical-study-reports? , m5-clinical-studyreports?)>
<!ATTLIST ectd:ectd xmlns:ectd CDATA #FIXED 'http://www.ich.org/ectd'
xmlns:xlink CDATA #FIXED 'http://www.w3c.org/1999/xlink'
xml:lang CDATA #IMPLIED
dtd-version CDATA #FIXED '3.2' >
<!-- ============================================================= -->
<!-- Leaf content -->
<!-- ============================================================= -->
<!ELEMENT leaf (title , link-text?)>
<!ATTLIST leaf ID
ID #REQUIRED
application-version CDATA #IMPLIED
version
CDATA #IMPLIED
font-library
CDATA #IMPLIED
operation
(new | append | replace | delete ) #REQUIRED
modified-file
CDATA #IMPLIED
checksum
CDATA #REQUIRED
checksum-type
CDATA #REQUIRED
keywords
CDATA #IMPLIED
xmlns:xlink
CDATA #FIXED 'http://www.w3c.org/1999/xlink'
xlink:type
CDATA #FIXED 'simple'
xlink:role
CDATA #IMPLIED
xlink:href
CDATA #IMPLIED
xlink:show
(new | replace | embed | other | none ) #IMPLIED
xlink:actuate
(onLoad | onRequest | other | none ) #IMPLIED
xml:lang
CDATA #IMPLIED >
<!ELEMENT title (#PCDATA)>
<!ATTLIST title ID ID #IMPLIED >
<!ELEMENT link-text (#PCDATA | xref)*>
<!ATTLIST link-text ID ID #IMPLIED >
<!ELEMENT xref EMPTY>
<!ATTLIST xref ID
ID #REQUIRED
xmlns:xlink CDATA #FIXED 'http://www.w3c.org/1999/xlink'
xlink:type CDATA #FIXED 'simple'
xlink:role CDATA #IMPLIED
xlink:title CDATA #REQUIRED
xlink:href CDATA #REQUIRED
xlink:show (new | replace | embed | other | none ) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none ) #IMPLIED >
<!ELEMENT node-extension (title , (leaf | node-extension)+)>
<!ATTLIST node-extension ID

Page 8-2

ID

#IMPLIED

xml:lang CDATA #IMPLIED >


<!-- ============================================================= -->
<!-- CTD Backbone structures -->
<!-- ============================================================= -->
<!ELEMENT m1-administrative-information-and-prescribing-information (leaf*)>
<!ATTLIST m1-administrative-information-and-prescribing-information %att; >
<!ELEMENT m2-common-technical-document-summaries (leaf* , m2-2-introduction? , m2-3-qualityoverall-summary? , m2-4-nonclinical-overview? , m2-5-clinical-overview? , m2-6-nonclinical-written-andtabulated-summaries? , m2-7-clinical-summary?)>
<!ATTLIST m2-common-technical-document-summaries %att; >
<!ELEMENT m2-2-introduction ((leaf | node-extension)*)>
<!ATTLIST m2-2-introduction %att; >
<!ELEMENT m2-3-quality-overall-summary (leaf* , m2-3-introduction? , m2-3-s-drug-substance* , m2-3p-drug-product* , m2-3-a-appendices? , m2-3-r-regional-information?)>
<!ATTLIST m2-3-quality-overall-summary %att; >
<!ELEMENT m2-3-introduction ((leaf | node-extension)*)>
<!ATTLIST m2-3-introduction %att; >
<!ELEMENT m2-3-s-drug-substance ((leaf | node-extension)*)>
<!ATTLIST m2-3-s-drug-substance %att;
substance CDATA #REQUIRED
manufacturer CDATA #REQUIRED >
<!ELEMENT m2-3-p-drug-product ((leaf | node-extension)*)>
<!ATTLIST m2-3-p-drug-product %att;
product-name CDATA #IMPLIED
dosageform CDATA #IMPLIED
manufacturer CDATA #IMPLIED >
<!ELEMENT m2-3-a-appendices ((leaf | node-extension)*)>
<!ATTLIST m2-3-a-appendices %att; >
<!ELEMENT m2-3-r-regional-information ((leaf | node-extension)*)>
<!ATTLIST m2-3-r-regional-information %att; >
<!ELEMENT m2-4-nonclinical-overview ((leaf | node-extension)*)>
<!ATTLIST m2-4-nonclinical-overview %att; >
<!ELEMENT m2-5-clinical-overview ((leaf | node-extension)*)>
<!ATTLIST m2-5-clinical-overview %att; >
<!ELEMENT m2-6-nonclinical-written-and-tabulated-summaries (leaf* , m2-6-1-introduction? , m2-6-2pharmacology-written-summary? , m2-6-3-pharmacology-tabulated-summary? , m2-6-4-pharmacokineticswritten-summary? , m2-6-5-pharmacokinetics-tabulated-summary? , m2-6-6-toxicology-written-summary?
, m2-6-7-toxicology-tabulated-summary?)>
<!ATTLIST m2-6-nonclinical-written-and-tabulated-summaries %att; >
<!ELEMENT m2-6-1-introduction ((leaf | node-extension)*)>
<!ATTLIST m2-6-1-introduction %att; >
<!ELEMENT m2-6-2-pharmacology-written-summary ((leaf | node-extension)*)>

Page 8-3

<!ATTLIST m2-6-2-pharmacology-written-summary %att; >


<!ELEMENT m2-6-3-pharmacology-tabulated-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-3-pharmacology-tabulated-summary %att; >
<!ELEMENT m2-6-4-pharmacokinetics-written-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-4-pharmacokinetics-written-summary %att; >
<!ELEMENT m2-6-5-pharmacokinetics-tabulated-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-5-pharmacokinetics-tabulated-summary %att; >
<!ELEMENT m2-6-6-toxicology-written-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-6-toxicology-written-summary %att; >
<!ELEMENT m2-6-7-toxicology-tabulated-summary ((leaf | node-extension)*)>
<!ATTLIST m2-6-7-toxicology-tabulated-summary %att; >
<!ELEMENT m2-7-clinical-summary (leaf* , m2-7-1-summary-of-biopharmaceutic-studies-andassociated-analytical-methods? , m2-7-2-summary-of-clinical-pharmacology-studies? , m2-7-3-summaryof-clinical-efficacy* , m2-7-4-summary-of-clinical-safety? , m2-7-5-literature-references? , m2-7-6synopses-of-individual-studies?)>
<!ATTLIST m2-7-clinical-summary %att; >
<!ELEMENT m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analytical-methods ((leaf |
node-extension)*)>
<!ATTLIST m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analytical-methods %att; >
<!ELEMENT m2-7-2-summary-of-clinical-pharmacology-studies ((leaf | node-extension)*)>
<!ATTLIST m2-7-2-summary-of-clinical-pharmacology-studies %att; >
<!ELEMENT m2-7-3-summary-of-clinical-efficacy ((leaf | node-extension)*)>
<!ATTLIST m2-7-3-summary-of-clinical-efficacy %att;
indication CDATA #REQUIRED >
<!ELEMENT m2-7-4-summary-of-clinical-safety ((leaf | node-extension)*)>
<!ATTLIST m2-7-4-summary-of-clinical-safety %att; >
<!ELEMENT m2-7-5-literature-references ((leaf | node-extension)*)>
<!ATTLIST m2-7-5-literature-references %att; >
<!ELEMENT m2-7-6-synopses-of-individual-studies ((leaf | node-extension)*)>
<!ATTLIST m2-7-6-synopses-of-individual-studies %att; >
<!ELEMENT m3-quality (leaf* , m3-2-body-of-data? , m3-3-literature-references?)>
<!ATTLIST m3-quality %att; >
<!ELEMENT m3-2-body-of-data (leaf* , m3-2-s-drug-substance* , m3-2-p-drug-product* , m3-2-aappendices? , m3-2-r-regional-information?)>
<!ATTLIST m3-2-body-of-data %att; >
<!ELEMENT m3-2-s-drug-substance (leaf* , m3-2-s-1-general-information? , m3-2-s-2-manufacture? ,
m3-2-s-3-characterisation? , m3-2-s-4-control-of-drug-substance? , m3-2-s-5-reference-standards-ormaterials? , m3-2-s-6-container-closure-system? , m3-2-s-7-stability?)>
<!ATTLIST m3-2-s-drug-substance %att;
substance CDATA #REQUIRED
manufacturer CDATA #REQUIRED >

Page 8-4

<!ELEMENT m3-2-s-1-general-information (leaf* , m3-2-s-1-1-nomenclature? , m3-2-s-1-2-structure? ,


m3-2-s-1-3-general-properties?)>
<!ATTLIST m3-2-s-1-general-information %att; >
<!ELEMENT m3-2-s-1-1-nomenclature ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-1-1-nomenclature %att; >
<!ELEMENT m3-2-s-1-2-structure ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-1-2-structure %att; >
<!ELEMENT m3-2-s-1-3-general-properties ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-1-3-general-properties %att; >
<!ELEMENT m3-2-s-2-manufacture (leaf* , m3-2-s-2-1-manufacturer? , m3-2-s-2-2-description-ofmanufacturing-process-and-process-controls? , m3-2-s-2-3-control-of-materials? , m3-2-s-2-4-controls-ofcritical-steps-and-intermediates? , m3-2-s-2-5-process-validation-and-or-evaluation? , m3-2-s-2-6manufacturing-process-development?)>
<!ATTLIST m3-2-s-2-manufacture %att; >
<!ELEMENT m3-2-s-2-1-manufacturer ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-1-manufacturer %att; >
<!ELEMENT m3-2-s-2-2-description-of-manufacturing-process-and-process-controls ((leaf | nodeextension)*)>
<!ATTLIST m3-2-s-2-2-description-of-manufacturing-process-and-process-controls %att; >
<!ELEMENT m3-2-s-2-3-control-of-materials ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-3-control-of-materials %att; >
<!ELEMENT m3-2-s-2-4-controls-of-critical-steps-and-intermediates ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-4-controls-of-critical-steps-and-intermediates %att; >
<!ELEMENT m3-2-s-2-5-process-validation-and-or-evaluation ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-5-process-validation-and-or-evaluation %att; >
<!ELEMENT m3-2-s-2-6-manufacturing-process-development ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-2-6-manufacturing-process-development %att; >
<!ELEMENT m3-2-s-3-characterisation (leaf* , m3-2-s-3-1-elucidation-of-structure-and-othercharacteristics? , m3-2-s-3-2-impurities?)>
<!ATTLIST m3-2-s-3-characterisation %att; >
<!ELEMENT m3-2-s-3-1-elucidation-of-structure-and-other-characteristics ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-3-1-elucidation-of-structure-and-other-characteristics %att; >
<!ELEMENT m3-2-s-3-2-impurities ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-3-2-impurities %att; >
<!ELEMENT m3-2-s-4-control-of-drug-substance (leaf* , m3-2-s-4-1-specification? , m3-2-s-4-2analytical-procedures? , m3-2-s-4-3-validation-of-analytical-procedures? , m3-2-s-4-4-batch-analyses? ,
m3-2-s-4-5-justification-of-specification?)>
<!ATTLIST m3-2-s-4-control-of-drug-substance %att; >
<!ELEMENT m3-2-s-4-1-specification ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-1-specification %att; >

Page 8-5

<!ELEMENT m3-2-s-4-2-analytical-procedures ((leaf | node-extension)*)>


<!ATTLIST m3-2-s-4-2-analytical-procedures %att; >
<!ELEMENT m3-2-s-4-3-validation-of-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-3-validation-of-analytical-procedures %att; >
<!ELEMENT m3-2-s-4-4-batch-analyses ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-4-batch-analyses %att; >
<!ELEMENT m3-2-s-4-5-justification-of-specification ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-4-5-justification-of-specification %att; >
<!ELEMENT m3-2-s-5-reference-standards-or-materials ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-5-reference-standards-or-materials %att; >
<!ELEMENT m3-2-s-6-container-closure-system ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-6-container-closure-system %att; >
<!ELEMENT m3-2-s-7-stability (leaf* , m3-2-s-7-1-stability-summary-and-conclusions? , m3-2-s-7-2post-approval-stability-protocol-and-stability-commitment? , m3-2-s-7-3-stability-data?)>
<!ATTLIST m3-2-s-7-stability %att; >
<!ELEMENT m3-2-s-7-1-stability-summary-and-conclusions ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-7-1-stability-summary-and-conclusions %att; >
<!ELEMENT m3-2-s-7-2-post-approval-stability-protocol-and-stability-commitment ((leaf | nodeextension)*)>
<!ATTLIST m3-2-s-7-2-post-approval-stability-protocol-and-stability-commitment %att; >
<!ELEMENT m3-2-s-7-3-stability-data ((leaf | node-extension)*)>
<!ATTLIST m3-2-s-7-3-stability-data %att; >
<!ELEMENT m3-2-p-drug-product (leaf* , m3-2-p-1-description-and-composition-of-the-drug-product? ,
m3-2-p-2-pharmaceutical-development? , m3-2-p-3-manufacture? , m3-2-p-4-control-of-excipients* , m32-p-5-control-of-drug-product? , m3-2-p-6-reference-standards-or-materials? , m3-2-p-7-container-closuresystem? , m3-2-p-8-stability?)>
<!ATTLIST m3-2-p-drug-product %att;
product-name CDATA #IMPLIED
dosageform CDATA #IMPLIED
manufacturer CDATA #IMPLIED >
<!ELEMENT m3-2-p-1-description-and-composition-of-the-drug-product ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-1-description-and-composition-of-the-drug-product %att; >
<!ELEMENT m3-2-p-2-pharmaceutical-development ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-2-pharmaceutical-development %att; >
<!ELEMENT m3-2-p-3-manufacture (leaf* , m3-2-p-3-1-manufacturers? , m3-2-p-3-2-batch-formula? ,
m3-2-p-3-3-description-of-manufacturing-process-and-process-controls? , m3-2-p-3-4-controls-of-criticalsteps-and-intermediates? , m3-2-p-3-5-process-validation-and-or-evaluation?)>
<!ATTLIST m3-2-p-3-manufacture %att; >
<!ELEMENT m3-2-p-3-1-manufacturers ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-3-1-manufacturers %att; >
<!ELEMENT m3-2-p-3-2-batch-formula ((leaf | node-extension)*)>

Page 8-6

<!ATTLIST m3-2-p-3-2-batch-formula %att; >


<!ELEMENT m3-2-p-3-3-description-of-manufacturing-process-and-process-controls ((leaf | nodeextension)*)>
<!ATTLIST m3-2-p-3-3-description-of-manufacturing-process-and-process-controls %att; >
<!ELEMENT m3-2-p-3-4-controls-of-critical-steps-and-intermediates ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-3-4-controls-of-critical-steps-and-intermediates %att; >
<!ELEMENT m3-2-p-3-5-process-validation-and-or-evaluation ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-3-5-process-validation-and-or-evaluation %att; >
<!ELEMENT m3-2-p-4-control-of-excipients (leaf* , m3-2-p-4-1-specifications? , m3-2-p-4-2-analyticalprocedures? , m3-2-p-4-3-validation-of-analytical-procedures? , m3-2-p-4-4-justification-of-specifications?
, m3-2-p-4-5-excipients-of-human-or-animal-origin? , m3-2-p-4-6-novel-excipients?)>
<!ATTLIST m3-2-p-4-control-of-excipients %att;
excipient CDATA #IMPLIED >
<!ELEMENT m3-2-p-4-1-specifications ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-1-specifications %att; >
<!ELEMENT m3-2-p-4-2-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-2-analytical-procedures %att; >
<!ELEMENT m3-2-p-4-3-validation-of-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-3-validation-of-analytical-procedures %att; >
<!ELEMENT m3-2-p-4-4-justification-of-specifications ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-4-justification-of-specifications %att; >
<!ELEMENT m3-2-p-4-5-excipients-of-human-or-animal-origin ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-5-excipients-of-human-or-animal-origin %att; >
<!ELEMENT m3-2-p-4-6-novel-excipients ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-4-6-novel-excipients %att; >
<!ELEMENT m3-2-p-5-control-of-drug-product (leaf* , m3-2-p-5-1-specifications? , m3-2-p-5-2analytical-procedures? , m3-2-p-5-3-validation-of-analytical-procedures? , m3-2-p-5-4-batch-analyses? ,
m3-2-p-5-5-characterisation-of-impurities? , m3-2-p-5-6-justification-of-specifications?)>
<!ATTLIST m3-2-p-5-control-of-drug-product %att; >
<!ELEMENT m3-2-p-5-1-specifications ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-1-specifications %att; >
<!ELEMENT m3-2-p-5-2-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-2-analytical-procedures %att; >
<!ELEMENT m3-2-p-5-3-validation-of-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-3-validation-of-analytical-procedures %att; >
<!ELEMENT m3-2-p-5-4-batch-analyses ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-4-batch-analyses %att; >
<!ELEMENT m3-2-p-5-5-characterisation-of-impurities ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-5-characterisation-of-impurities %att; >

Page 8-7

<!ELEMENT m3-2-p-5-6-justification-of-specifications ((leaf | node-extension)*)>


<!ATTLIST m3-2-p-5-6-justification-of-specifications %att; >
<!ELEMENT m3-2-p-6-reference-standards-or-materials ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-6-reference-standards-or-materials %att; >
<!ELEMENT m3-2-p-7-container-closure-system ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-7-container-closure-system %att; >
<!ELEMENT m3-2-p-8-stability (leaf* , m3-2-p-8-1-stability-summary-and-conclusion? , m3-2-p-8-2post-approval-stability-protocol-and-stability-commitment? , m3-2-p-8-3-stability-data?)>
<!ATTLIST m3-2-p-8-stability %att; >
<!ELEMENT m3-2-p-8-1-stability-summary-and-conclusion ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-8-1-stability-summary-and-conclusion %att; >
<!ELEMENT m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment ((leaf | nodeextension)*)>
<!ATTLIST m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment %att; >
<!ELEMENT m3-2-p-8-3-stability-data ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-8-3-stability-data %att; >
<!ELEMENT m3-2-a-appendices (leaf* , m3-2-a-1-facilities-and-equipment* , m3-2-a-2-adventitiousagents-safety-evaluation* , m3-2-a-3-excipients?)>
<!ATTLIST m3-2-a-appendices %att; >
<!ELEMENT m3-2-a-1-facilities-and-equipment ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-1-facilities-and-equipment %att;
manufacturer CDATA #IMPLIED
substance CDATA #IMPLIED
dosageform CDATA #IMPLIED
product-name CDATA #IMPLIED >
<!ELEMENT m3-2-a-2-adventitious-agents-safety-evaluation ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-2-adventitious-agents-safety-evaluation %att;
manufacturer CDATA #IMPLIED
substance CDATA #IMPLIED
dosageform CDATA #IMPLIED
product-name CDATA #IMPLIED >
<!ELEMENT m3-2-a-3-excipients ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-3-excipients %att; >
<!ELEMENT m3-2-r-regional-information ((leaf | node-extension)*)>
<!ATTLIST m3-2-r-regional-information %att; >
<!ELEMENT m3-3-literature-references ((leaf | node-extension)*)>
<!ATTLIST m3-3-literature-references %att; >
<!ELEMENT m4-nonclinical-study-reports (leaf* , m4-2-study-reports? , m4-3-literature-references?)>
<!ATTLIST m4-nonclinical-study-reports %att; >
<!ELEMENT m4-2-study-reports (leaf* , m4-2-1-pharmacology? , m4-2-2-pharmacokinetics? , m4-2-3toxicology?)>

Page 8-8

<!ATTLIST m4-2-study-reports %att; >


<!ELEMENT m4-2-1-pharmacology (leaf* , m4-2-1-1-primary-pharmacodynamics? , m4-2-1-2secondary-pharmacodynamics? , m4-2-1-3-safety-pharmacology? , m4-2-1-4-pharmacodynamic-druginteractions?)>
<!ATTLIST m4-2-1-pharmacology %att; >
<!ELEMENT m4-2-1-1-primary-pharmacodynamics ((leaf | node-extension)*)>
<!ATTLIST m4-2-1-1-primary-pharmacodynamics %att; >
<!ELEMENT m4-2-1-2-secondary-pharmacodynamics ((leaf | node-extension)*)>
<!ATTLIST m4-2-1-2-secondary-pharmacodynamics %att; >
<!ELEMENT m4-2-1-3-safety-pharmacology ((leaf | node-extension)*)>
<!ATTLIST m4-2-1-3-safety-pharmacology %att; >
<!ELEMENT m4-2-1-4-pharmacodynamic-drug-interactions ((leaf | node-extension)*)>
<!ATTLIST m4-2-1-4-pharmacodynamic-drug-interactions %att; >
<!ELEMENT m4-2-2-pharmacokinetics (leaf* , m4-2-2-1-analytical-methods-and-validation-reports? ,
m4-2-2-2-absorption? , m4-2-2-3-distribution? , m4-2-2-4-metabolism? , m4-2-2-5-excretion? , m4-2-2-6pharmacokinetic-drug-interactions? , m4-2-2-7-other-pharmacokinetic-studies?)>
<!ATTLIST m4-2-2-pharmacokinetics %att; >
<!ELEMENT m4-2-2-1-analytical-methods-and-validation-reports ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-1-analytical-methods-and-validation-reports %att; >
<!ELEMENT m4-2-2-2-absorption ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-2-absorption %att; >
<!ELEMENT m4-2-2-3-distribution ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-3-distribution %att; >
<!ELEMENT m4-2-2-4-metabolism ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-4-metabolism %att; >
<!ELEMENT m4-2-2-5-excretion ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-5-excretion %att; >
<!ELEMENT m4-2-2-6-pharmacokinetic-drug-interactions ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-6-pharmacokinetic-drug-interactions %att; >
<!ELEMENT m4-2-2-7-other-pharmacokinetic-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-2-7-other-pharmacokinetic-studies %att; >
<!ELEMENT m4-2-3-toxicology (leaf* , m4-2-3-1-single-dose-toxicity? , m4-2-3-2-repeat-dose-toxicity? ,
m4-2-3-3-genotoxicity? , m4-2-3-4-carcinogenicity? , m4-2-3-5-reproductive-and-developmental-toxicity?
, m4-2-3-6-local-tolerance? , m4-2-3-7-other-toxicity-studies?)>
<!ATTLIST m4-2-3-toxicology %att; >
<!ELEMENT m4-2-3-1-single-dose-toxicity ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-1-single-dose-toxicity %att; >
<!ELEMENT m4-2-3-2-repeat-dose-toxicity ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-2-repeat-dose-toxicity %att; >
<!ELEMENT m4-2-3-3-genotoxicity (leaf* , m4-2-3-3-1-in-vitro? , m4-2-3-3-2-in-vivo?)>

Page 8-9

<!ATTLIST m4-2-3-3-genotoxicity %att; >


<!ELEMENT m4-2-3-3-1-in-vitro ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-3-1-in-vitro %att; >
<!ELEMENT m4-2-3-3-2-in-vivo ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-3-2-in-vivo %att; >
<!ELEMENT m4-2-3-4-carcinogenicity (leaf* , m4-2-3-4-1-long-term-studies? , m4-2-3-4-2-short-ormedium-term-studies? , m4-2-3-4-3-other-studies?)>
<!ATTLIST m4-2-3-4-carcinogenicity %att; >
<!ELEMENT m4-2-3-4-1-long-term-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-4-1-long-term-studies %att; >
<!ELEMENT m4-2-3-4-2-short-or-medium-term-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-4-2-short-or-medium-term-studies %att; >
<!ELEMENT m4-2-3-4-3-other-studies ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-4-3-other-studies %att; >
<!ELEMENT m4-2-3-5-reproductive-and-developmental-toxicity (leaf* , m4-2-3-5-1-fertility-and-earlyembryonic-development? , m4-2-3-5-2-embryo-fetal-development? , m4-2-3-5-3-prenatal-and-postnataldevelopment-including-maternal-function? , m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animalsare-dosed-and-or-further-evaluated?)>
<!ATTLIST m4-2-3-5-reproductive-and-developmental-toxicity %att; >
<!ELEMENT m4-2-3-5-1-fertility-and-early-embryonic-development ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-1-fertility-and-early-embryonic-development %att; >
<!ELEMENT m4-2-3-5-2-embryo-fetal-development ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-2-embryo-fetal-development %att; >
<!ELEMENT m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function ((leaf | nodeextension)*)>
<!ATTLIST m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function %att; >
<!ELEMENT m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-furtherevaluated ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-furtherevaluated %att; >
<!ELEMENT m4-2-3-6-local-tolerance ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-6-local-tolerance %att; >
<!ELEMENT m4-2-3-7-other-toxicity-studies (leaf* , m4-2-3-7-1-antigenicity? , m4-2-3-7-2immunotoxicity? , m4-2-3-7-3-mechanistic-studies? , m4-2-3-7-4-dependence? , m4-2-3-7-5-metabolites? ,
m4-2-3-7-6-impurities? , m4-2-3-7-7-other?)>
<!ATTLIST m4-2-3-7-other-toxicity-studies %att; >
<!ELEMENT m4-2-3-7-1-antigenicity ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-1-antigenicity %att; >
<!ELEMENT m4-2-3-7-2-immunotoxicity ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-2-immunotoxicity %att; >

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<!ELEMENT m4-2-3-7-3-mechanistic-studies ((leaf | node-extension)*)>


<!ATTLIST m4-2-3-7-3-mechanistic-studies %att; >
<!ELEMENT m4-2-3-7-4-dependence ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-4-dependence %att; >
<!ELEMENT m4-2-3-7-5-metabolites ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-5-metabolites %att; >
<!ELEMENT m4-2-3-7-6-impurities ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-6-impurities %att; >
<!ELEMENT m4-2-3-7-7-other ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-7-7-other %att; >
<!ELEMENT m4-3-literature-references ((leaf | node-extension)*)>
<!ATTLIST m4-3-literature-references %att; >
<!ELEMENT m5-clinical-study-reports (leaf* , m5-2-tabular-listing-of-all-clinical-studies? , m5-3-clinicalstudy-reports? , m5-4-literature-references?)>
<!ATTLIST m5-clinical-study-reports %att; >
<!ELEMENT m5-2-tabular-listing-of-all-clinical-studies ((leaf | node-extension)*)>
<!ATTLIST m5-2-tabular-listing-of-all-clinical-studies %att; >
<!ELEMENT m5-3-clinical-study-reports (leaf* , m5-3-1-reports-of-biopharmaceutic-studies? , m5-3-2reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials? , m5-3-3-reports-of-humanpharmacokinetics-pk-studies? , m5-3-4-reports-of-human-pharmacodynamics-pd-studies? , m5-3-5-reportsof-efficacy-and-safety-studies* , m5-3-6-reports-of-postmarketing-experience? , m5-3-7-case-report-formsand-individual-patient-listings?)>
<!ATTLIST m5-3-clinical-study-reports %att; >
<!ELEMENT m5-3-1-reports-of-biopharmaceutic-studies (leaf* , m5-3-1-1-bioavailability-study-reports? ,
m5-3-1-2-comparative-ba-and-bioequivalence-study-reports? , m5-3-1-3-in-vitro-in-vivo-correlation-studyreports? , m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies?)>
<!ATTLIST m5-3-1-reports-of-biopharmaceutic-studies %att; >
<!ELEMENT m5-3-1-1-bioavailability-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-1-1-bioavailability-study-reports %att; >
<!ELEMENT m5-3-1-2-comparative-ba-and-bioequivalence-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-1-2-comparative-ba-and-bioequivalence-study-reports %att; >
<!ELEMENT m5-3-1-3-in-vitro-in-vivo-correlation-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-1-3-in-vitro-in-vivo-correlation-study-reports %att; >
<!ELEMENT m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies ((leaf | nodeextension)*)>
<!ATTLIST m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies %att; >
<!ELEMENT m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials (leaf* ,
m5-3-2-1-plasma-protein-binding-study-reports? , m5-3-2-2-reports-of-hepatic-metabolism-and-druginteraction-studies? , m5-3-2-3-reports-of-studies-using-other-human-biomaterials?)>
<!ATTLIST m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials %att; >
<!ELEMENT m5-3-2-1-plasma-protein-binding-study-reports ((leaf | node-extension)*)>

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<!ATTLIST m5-3-2-1-plasma-protein-binding-study-reports %att; >


<!ELEMENT m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies ((leaf | nodeextension)*)>
<!ATTLIST m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies %att; >
<!ELEMENT m5-3-2-3-reports-of-studies-using-other-human-biomaterials ((leaf | node-extension)*)>
<!ATTLIST m5-3-2-3-reports-of-studies-using-other-human-biomaterials %att; >
<!ELEMENT m5-3-3-reports-of-human-pharmacokinetics-pk-studies (leaf* , m5-3-3-1-healthy-subject-pkand-initial-tolerability-study-reports? , m5-3-3-2-patient-pk-and-initial-tolerability-study-reports? , m5-3-33-intrinsic-factor-pk-study-reports? , m5-3-3-4-extrinsic-factor-pk-study-reports? , m5-3-3-5-populationpk-study-reports?)>
<!ATTLIST m5-3-3-reports-of-human-pharmacokinetics-pk-studies %att; >
<!ELEMENT m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports %att; >
<!ELEMENT m5-3-3-2-patient-pk-and-initial-tolerability-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-2-patient-pk-and-initial-tolerability-study-reports %att; >
<!ELEMENT m5-3-3-3-intrinsic-factor-pk-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-3-intrinsic-factor-pk-study-reports %att; >
<!ELEMENT m5-3-3-4-extrinsic-factor-pk-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-4-extrinsic-factor-pk-study-reports %att; >
<!ELEMENT m5-3-3-5-population-pk-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-3-5-population-pk-study-reports %att; >
<!ELEMENT m5-3-4-reports-of-human-pharmacodynamics-pd-studies (leaf* , m5-3-4-1-healthy-subjectpd-and-pk-pd-study-reports? , m5-3-4-2-patient-pd-and-pk-pd-study-reports?)>
<!ATTLIST m5-3-4-reports-of-human-pharmacodynamics-pd-studies %att; >
<!ELEMENT m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports %att; >
<!ELEMENT m5-3-4-2-patient-pd-and-pk-pd-study-reports ((leaf | node-extension)*)>
<!ATTLIST m5-3-4-2-patient-pd-and-pk-pd-study-reports %att; >
<!ELEMENT m5-3-5-reports-of-efficacy-and-safety-studies (leaf* , m5-3-5-1-study-reports-of-controlledclinical-studies-pertinent-to-the-claimed-indication? , m5-3-5-2-study-reports-of-uncontrolled-clinicalstudies? , m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study? , m5-3-5-4-other-studyreports?)>
<!ATTLIST m5-3-5-reports-of-efficacy-and-safety-studies %att;
indication CDATA #REQUIRED >
<!ELEMENT m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
((leaf | node-extension)*)>
<!ATTLIST m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
%att; >
<!ELEMENT m5-3-5-2-study-reports-of-uncontrolled-clinical-studies ((leaf | node-extension)*)>
<!ATTLIST m5-3-5-2-study-reports-of-uncontrolled-clinical-studies %att; >
<!ELEMENT m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study ((leaf | node-extension)*)>

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<!ATTLIST m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study %att; >


<!ELEMENT m5-3-5-4-other-study-reports ((leaf | node-extens