ECTD Digital Handbook PDF

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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 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 CRF’s 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 CTD–General guidance on summaries–Annex: 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 authority-
specific 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 guidance–continuation 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 Analysis–5.3.5.3 Reports of analyses of data from more than one
study–Module 5 provides necessary organization structures through STF.
o Module 2 Summaries–Critical and Concise Summaries–Page counts do not define what’s
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 FDA’s 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 document’s 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 FDA’s 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 suc-
cessful 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. eCTD: Module 1, Bronwyn Collier, FDA

2. eCTD Guidance Overview, Gary M. Gensinger, MBA, FDA
3. Ensuring a Effective Submission, Gary M. Gensinger, MBA, FDA
4. Guidance Compliant eCTDs Module 4: Safety, Steve Wilson, DrPH, CAPT USPHS, FDA
5. Guidance-Compliant eCTDs: Module 5, Armando Oliva, M.D., FDA
6. eCTDs Quality/CMC Issues, Norman R. Schmuff, Ph.D., FDA
7. 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
2
Module 1: Purpose
• Archive regional documents
• Application management
– Status
– Business
– Special regulatory programs
– Provides the legal and regulatory framework
for the application/submission
3
Impact on Review Process
• Facilitates document processing
– Identification
– Division assignment
• Review assignment
• Guides response
• Satisfies some regulatory requirements
4
TOC Mapping
CFR Citation eCTD/STF Heading
NUMBER TITLE MODULE NUMBER TITLE
312.7(d) Charging for and 1 1.12.2 Request to
commercialization Charge
of investigational
drugs
312.10 Waivers 1 1.12.5 Request for a
waiver
312.23 Cover sheet (Form 1 1.1.1 Application

(a)(1) FDA 1571) form: FDA form
1571
312.23(a)(2) Table of Contents N/A N/A N/A
314.50(h) Patent Information 1 1.3.5.1 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
7
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
9
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 Investigator’s 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
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
Using eCTD Specifications

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 doesn’t 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 don’t do it…
• Don’t send electronic submissions to
the division document rooms
• Don’t use node extensions in preparing
eCTD
• Don’t combine multiple documents into
single PDF
• Don’t send customized style sheets
• Don’t 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
• 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

esub@cder.fda.gov
Remember!
• One of your goals is communication

– Clarity improves reviewability
– Consider application from reviewer’s
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. Files Referenced in the XML Backbone(s)
9. eCTD Submissions Include Module 1
8. Application Numbers are 6 Digits
7. Sequence Numbers are 4 Digits
6. Unneeded Node Extensions are Removed
5. MD5 Checksum are Correct
4. Documents Conform to eCTD Granularity
3. XML must be Standard Components
2. PDF Hyperlinks/Bookmarks are Correct
1. 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 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 FDA’s 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

and CTD submissions eSub@cder.fda.gov
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.
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
• 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
• Data tabulation
– Data tabulation datasets
– Data definitions
• Data listing datasets
– Data listing datasets
• Analysis datasets
– Analysis datasets
– Analysis programs
• 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)?
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.
• FDA’s 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.
• 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.
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

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 CRF’s organized by study, but still XPT and PDF, respectively.
Guidance-Compliant eCTDs:
Module 5
Armando Oliva, M.D.

Associate Director for Policy
Company
Office of New Drugs logo here
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 dose 10 5.3.3.1
1 mg 10
5 mg 10
10 mg 10
AA-002 [Title2] Placebo 2 weeks 10 5.3.3.1
1 mg q d 20
5 mg q d 20
PD
Studies
AB-001 [Title 3] Placebo 1 week 10 5.3.4.2
5 mg qd 15
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 • Healthy Subject /
• Bioequivalence (BE) • Hepatic Metabolism Patient PK
• In-vitro/in-vivo • Drug Interaction • Intrinsic Factor PK

correlation • Extrinsic Factor PK
• In-vitro/in-vivo
•Bioanalytical/Analytical correlation studies • Population PK
Methods for Human
•Bioanalytical/Analytical
Studies
Methods for Human
Studies
5.3.4
Human PD
• Healthy Subject PD and PK/PD
esub@cder.fda.gov
5.3.5 5.3.6
Efficacy and Safety Studies Postmarketing Experience

(Indication) • Postmarketing periodic adverse
• Controlled studies pertinent to claim 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; Investigator’s
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 CRF’s 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
Tyson’s 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>
<to id=“123”> Bill Monroe </to> memo is comprised of “child” elements,
cc which
date, may appear
to, from, zero must
which or more times
appear and
<from id=“345”> Maybelle Carter </from>
sub-topic may appear zero or just once
(i.e. optional
must be but
in canorder
the repeat indefinitely),
given, followed but
by if it
<cc> Bob Wills </cc> (i.e. optional, but cannot repeat )
the element to has appears
a required at all, ID
attribute it must
(ID isbe
a directly after the from
special XML
<topic> Picnic body must
</topic> appear at least once and
“attribute” required to be element
unique throughout an XML document, in this
can be repeated
case it is an employee’s
<lead-para> identification
Our annual picnic number)
is scheduled.. </lead-para>
<body> Some details follow... </body>
</memo> <!ELEMENT memo (date, to, from, cc*, topic,
sub-topic?, lead-para, body+)>
DTD
<!ELEMENT date (#PCDATA)>
<!ELEMENT to (#PCDATA)>
<!ATTLIST to ID #REQUIRED>
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: + one or more
From:
[CC:] * zero or more
Topic: ? zero or one
[Sub-topic:]
Lead paragraph
Body
Body
eCTD Required Elements


<!ELEMENT admin (applicant-info, product-description, application-information)>

<!ELEMENT applicant-info (company-name, date-of-submission)>
<!ELEMENT company-name (#PCDATA)>
<!ELEMENT date-of-submission (date)>
<!ATTLIST date
format (yyyymmdd) #REQUIRED
>

<!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 FDA’s Module 1 DTD

<!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 you’re
<!ATTLIST date nonecomments with
are optional), not 
</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 fda-
regional: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-of-
submission.
0. Company-name Element
The sponsor or applicant’s name is in the company-name element. An example of the company-
name 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:fda-
regional element.
Version 1.3 4
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 Product Name Type

type="established" Established name (e.g., proper name)
type="proprietary" Proprietary name (e.g., brand name, trade name)
type="chemical" Chemical name. (spell Greek characters and don't use
superscript or subscript)
type="code" Internal code used by the application sponsor.
Version 1.3 5
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

application-type="nda" New Drug Application
application-type="anda" Abbreviated New Drug Application
application-type="bla" Biologics License Application
application-type="ind" Investigational new drug application.
application-type="dmf" Master file
0. Submission Element
There are two elements in the submission element: sequence-number, and related-sequence-
number. 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 Meaning
Attribute Value
“original-application" A complete new application that has never before been submitted
"amendment" All submissions to pending original submission or pending
supplements to approved applications including responses to
information request letters
"resubmission" 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
"presubmission" Information submitted prior to the submission of a complete new
application
"annual-report" Annual Reports to applications
Version 1.3 6
Submission-type Meaning
Attribute Value
"establishment- Supplements to the information contained in the establishment
description-supplement" description section for biological products
"efficacy-supplement" 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
"labeling-supplement" All label change supplements required under 21 CFR 314.70 and 21
CFR 601.12 that do not qualify as efficacy supplements;
"chemistry- Manufacturing and Controls Supplement manufacturing change
manufacturing-controls- supplement submissions as provided in 21 CFR 314.70, 21 CFR
supplement" 314.71, 21 CFR 314.72 and 21 CFR 601.12
"other" 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 - Original application

0001 - an amendment to original application
0003 - a chemistry, manufacturing and control supplement
0005 - an amendment to the supplement
0006 - an amendment to the original application
0007 - an amendment that relates to both the original and supplement
A non-XML representation would relate this as:
Version 1.3 7
Sequence-number Related-sequence-number***
0000
0001 0000
0002 0000
0003
0004 0000
0005 0003
0006 0000
0007 0000 0003
Example XML coding for the original application would look like:
<submission submission-type="original-application">
</submission>
Example XML coding for a supplement to an original application would look like:
<submission submission-type="chemistry-manufacturing-controls-supplement ">

</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">
<related-sequence-number>0000</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">
</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
Version 1.3 8
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 Heading element (leaf element abbreviated

for clarity)
Regional information <m1-regional>
0. Forms <m1-1-forms>
Choose one of the following elements to contain
your form's leaf element.
<m1-1-1-fda-form-1571>
) Investigational New
<leaf>
Drug (IND)
</leaf>
</m1-1-1-fda-form-1571>
<m1-1-2-fda-form-356h>
) New Drug Application
<leaf>
(NDA) or New Biologic
</leaf>
Application (BLA)
</m1-1-2-fda-form-356h>
Version 1.3 9

for clarity)
<m1-1-3-fda-form-3397>
) User Fee Cover Sheet
<leaf>
</leaf>
</m1-1-3-fda-form-3397>
<m1-1-4-fda-form-2252>
) Annual Report
<leaf>
Transmittal
</leaf>
</m1-1-4-fda-form-2252>
<m1-1-5-fda-form-2253>
) Advertising and
<leaf>
Promotional Labeling
</leaf>
</m1-1-5-fda-form-2253>
) Transmittal of Labels <m1-1-6-fda-form-2567>
<leaf
and Circulars
</leaf>
</m1-1-6-fda-form-2567>
End of Forms </m1-1-forms>
0. Cover Letters <m1-2-cover-letters>
<leaf>
</leaf>
</m1-2-cover-letters>
0. Administrative Information <m1-3-administrative-information>
<m1-3-1-applicant-information>
) Applicant Information
<m1-3-1-1-cofa-con>
(0) Change of Address <leaf>
</leaf>
</m1-3-1-1-cofa-con>
<m1-3-1-2-change-contact-
(0) Change of Agent agent>
<leaf>
</leaf>
</m1-3-1-2-change-contact-
agent>
<m1-3-1-3-change-sponsor>
(0) Sponsor Change <leaf>
</leaf>
</m1-3-1-3-change-sponsor>
<m1-3-1-4-transfer-obligation>
(0) Obligation Transfer <leaf>
</leaf>
</m1-3-1-4-transfer-
obligation>
Version 1.3 10

for clarity)
<m1-3-1-5-change-application-
(0) Ownership Change ownership>
<leaf>
</leaf>
</m1-3-1-5-change-
application-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-certification-
disclosure>
<m1-3-5-patent-exclusivity>
) Patent Exclusivity
<m1-3-5-1-patent-information>
(0) Patent Information <leaf>
</leaf>
</m1-3-5-1-patent-
information>
<m1-3-5-2-patent-
(0) Patent Certification certification>
<leaf>
</leaf>
</m1-3-5-2-patent-
certification>
<m1-3-5-3-exclusivity-
(0) Exclusivity Request request>
<leaf>
</leaf>
</m1-3-5-3-exclusivity-
request>
End of Patent Exclusivity </m1-3-5-patent-exclusivity>
End of Administrative Information </m1-3-administrative-information>
0. Reference Section <m1-4-references>
Version 1.3 11

for clarity)
<m1-4-1-letter-authorization>
) Letter of Authorization
<leaf>
</leaf>
</m1-4-1-letter-authorization>
<m1-4-2-statement-right-
) Statement of Right to
reference>
Reference
<leaf>
</leaf>
</m1-4-2-statement-right-
reference>
<m1-4-3-list-authorized-persons-
) List of Authorized to
incorporate-reference>
Persons to Incorporate by
<leaf>
Reference
</leaf>
</m1-4-3-list-authorized-persons-
incorporate-reference>
<m1-4-4-cross-reference-other-
) Cross Reference to
applications>
Other Applications
<leaf>
</leaf>
</m1-4-4-cross-reference-other-
applications>
End References </m1-4-references>
0. Application Status <m1-5-application-status>
Documentation
<m1-5-1-withdrawal-request>
) Withdrawal Request
<leaf>
</leaf>
</m1-5-1-withdrawal-request>
<m1-5-2-inactivation-request>
) Inactivation Request
<leaf>
</leaf>
</m1-5-2-inactivation-request>
<m1-5-3-reactivation-request>
) Reactivation Request
<leaf>
</leaf>
</m1-5-3-reactivation-request>
<m1-5-4-reinstatement-request>
) Reinstatement Request
<leaf>
</leaf>
</m1-5-4-reinstatement-request>
Version 1.3 12

for clarity)
<m1-5-5-withdrawal-unapproved-
) Withdrawal of
nda>
Unapproved NDA
<leaf>
</leaf>
</m1-5-5-withdrawal-unapproved-
nda>
<m1-5-6-withdrawal-of-listed-
) Withdrawal of Listed
drug>
Drug
<leaf>
</leaf>
</m1-5-6-withdrawal-of-listed-
drug>
<m1-5-7-request-withdrawal-
) Request for Withdrawal
application-approval>
of Application Approval
<leaf>
</leaf>
</m1-5-7-request-withdrawal-
application-approval>
End Application Status </m1-5-application-status>
0. Meetings <m1-6-meetings>
<m1-6-1-meeting-request>
) Meeting Request
<leaf>
</leaf>
</m1-6-1-meeting-request>
<m1-6-2-meeting-background-
) Meeting Background
materials>
Materials
<leaf>
</leaf>
</m1-6-2-meeting-background-
materials>
<m1-6-3-correspondence-
) Correspondence
regarding-meetings>
Regarding Meetings
<leaf>
</leaf>
</m1-6-3-correspondence-
regarding-meetings>
End Meetings </m1-6-meetings>
0. Fast Track <m1-7-fast-track>
<m1-7-1-fast-track-designation-
) Fast Track Designation
request>
Request
<leaf>
</leaf>
</m1-7-1-fast-track-designation-
request>
Version 1.3 13

for clarity)
<m1-7-2-fast-track-designation-
) Fast Track Designation
withdrawal-request>
Withdrawal Request
<leaf>
</leaf>
</m1-7-2-fast-track-designation-
withdrawal-request>
<m1-7-3-rolling-review-request>
) Rolling Review Request
<leaf>
</leaf>
</m1-7-3-rolling-review-request>
End Fast Track </m1-7-fast-track>
0. Special Protocol Assessment <m1-8-special-protocol-assessment-
Request request>
<m1-8-1-clinical-study>
) Clinical Study
<leaf>
</leaf>
<m1-8-1-clinical-study>
<m1-8-2-carcinogenicity-study>
) Carcinogenicity Study
<leaf>
</leaf>
<m1-8-2-carcinogenicity-study>
<m1-8-3-stability-study>
) Stability Study
<leaf>
</leaf>
<m1-8-3-stability-study>
End Special Protocol </m1-8-special-protocol-assessment-
request>
0. Pediatric Administrative <m1-9-pediatric-administrative-
Information information>
<m1-9-1-request-waiver-pediatric-
) Request for Waiver of
studies>
Pediatric Studies
<leaf>
</leaf>
</m1-9-1-request-waiver-pediatric-
studies>
<m1-9-2-request-deferral-
) Request for Deferral of
pediatric-studies>
Pediatric Studies
<leaf>
</leaf>
</m1-9-2-request-deferral-
pediatric-studies>
Version 1.3 14

for clarity)
<m1-9-3-request-pediatric-
) Request for Pediatric
exclusivity-determination>
Exclusivity Determination
<leaf>
</leaf>
</m1-9-3-request-pediatric-
exclusivity-determination>
<m1-9-4-proposed-pediatric-study-
) Proposed Pediatric
request-amendments>
Study Request and
<leaf>
amendments
</leaf>
</m1-9-4-proposed-pediatric-
study-request-amendments>
<m1-9-5-proposal-written-
) Proposal for Written
agreement>
Agreement
<leaf>
</leaf>
</m1-9-5-proposal-written-
agreement>
<m1-9-6-other-correspondence-
) Other Correspondence
regarding-pediatric-exclusivity-
Regarding Pediatric
study-plans>
Exclusivity or Study Plans
<leaf>
</leaf>
</m1-9-6-other-correspondence-
regarding-pediatric-exclusivity-
study-plans>
End Pediatric <\m1-9-pediatric-administrative-
information>
0. Dispute Resolution <m1-10-dispute-resolution>
<m1-10-1-request-for-dispute-
) Request for Dispute
resolution>
Resolution
<leaf>
</leaf>
</m1-10-1-request-for-dispute-
resolution>
<m1-10-2-correspondence-related-
) Correspondence Related
to-dispute-resolution>
to Dispute Resolution
<leaf>
</leaf>
related-to-dispute-resolution>
End Dispute Resolution </m1-10-dispute-resolution>
0. Information Not Covered Under <m1-11-information-amendment>
Modules 2 to 5
Version 1.3 15

for clarity)
<m1-11-1-quality-information-
) Quality Information
amendment>
Amendment
<leaf>
</leaf>
</m1-11-1-quality-information-
amendment>
<m1-11-2-safety-information-
) Safety Information
amendment>
Amendment
<leaf>
</leaf>
</m1-11-2-safety-information-
amendment>
<m1-11-3-efficacy-information-
) Efficacy Information
amendment>
Amendment
<leaf>
</leaf>
</m1-11-3-efficacy-information-
amendment>
<m1-11-4-multiple-module-
) Multiple Module
information-amendments>
Information Amendments
<leaf>
</leaf>
</m1-11-4-multiple-module-
information-amendments>
End Modules </m1-11-information-amendment>
0. Other Correspondence <m1-12-other-correspondence>
<m1-12-1-pre-ind-
) Pre IND
correspondence>
Correspondence
<leaf>
</leaf>
</m1-12-1-pre-ind-
correspondence>
<m1-12-2-request-charge>
) Request to Charge
<leaf>
</leaf>
</m1-12-2-request-charge>
<m1-12-3-notification-charging-
) Notification of Charging
under-treatment-ind>
Under Treatment IND
<leaf>
</leaf>
</m1-12-3-notification-charging-
under-treatment-ind>
Version 1.3 16

for clarity)
<m1-12-4-request-comments-
) Request for Comments
advice-ind>
and Advice on an IND
<leaf>
</leaf>
</m1-12-4-request-comments-
advice-ind>
<m1-12-5-request-waiver>
) Request for Waiver
<leaf>
</leaf>
</m1-12-5-request-waiver>
<m1-12-6-exemption-informed-
) Exemption from
consent-emergency-research>
Informed Consent for
<leaf>
Emergency Research
</leaf>
</m1-12-6-exemption-informed-
consent-emergency-research>
<m1-12-7-public-disclosure-
) Public Disclosure
statement-emergency-care-
Statement for Emergency
research>
Care Research
<leaf>
</leaf>
</m1-12-7-public-disclosure-
statement-emergency-care-
research>
<m1-12-8-correspondence-
) Correspondence
regarding-emergency-care-
Regarding Emergency Care
research>
Research
<leaf>
</leaf>
regarding-emergency-care-
research>
<m1-12-9-notification-
) Notification of
discontinuation-clinical-trial>
Discontinuation of Clinical
<leaf>
Trial
</leaf>
</m1-12-9-notification-
discontinuation-clinical-trial>
<m1-12-10-generic-drug-
) Generic Drug
enforcement-act-statement>
Enforcement Act Statement
<leaf>
</leaf>
</m1-12-10-generic-drug-
enforcement-act-statement>
Version 1.3 17

for clarity)
<m1-12-11-basis-submission-
) Basis for Submission
statement>
Statement
<leaf>
</leaf>
</m1-12-11-basis-submission-
statement>
<m1-12-12-comparison-generic-
) Comparison of Generic
drug-reference-listed-drug>
Drug and Reference Listed
<leaf>
Drug
</leaf>
</m1-12-12-comparison-generic-
drug-reference-listed-drug>
<m1-12-13-request-waiver-in-
) Request for Waiver For
vivo-studies>
In Vivo Studies
<leaf>
</leaf>
</m1-12-13-request-waiver-in-
vivo-studies>
<m1-12-14-environmental-
) Environmental Analysis
analysis>
<leaf>
</leaf>
</m1-12-14-environmental-
analysis>
<m1-12-15-request-waiver-in-
) Request for Waiver of In
vivo-bioavailability-studies>
Vivo Bioavailability Studies
<leaf>
</leaf>
</m1-12-15-request-waiver-in-
vivo-bioavailability-studies>
<m1-12-16-field-alert-reports>
) Field Alert Reports
<leaf>
</leaf>
</m1-12-16-field-alert-reports>
End of correspondence </m1-12-other-correspondence>
0. Annual Report <m1-13-annual-report>
<m1-13-1-summary-nonclinical-
) Summary for
studies>
Nonclinical Studies
<leaf>
</leaf>
</m1-13-1-summary-nonclinical-
studies>
Version 1.3 18

for clarity)
<m1-13-2-summary-clinical-
) Summary for Clinical
pharmacology-information>
Pharmacology Information
<leaf>
</leaf>
</m1-13-2-summary-clinical-
pharmacology-information>
<m1-13-3-summary-safety-
) Summary of Safety
information>
Information
<leaf>
</leaf>
</m1-13-3-summary-safety-
information>
<m1-13-4-summary-labeling-
) Summary of Labeling
changes>
Changes
<leaf>
</leaf>
</m1-13-4-summary-labeling-
hanges>
) Summary of <m1-13-5-summary-of-
manufacturing changes manufacturing-changes>
<leaf>
</leaf>
</m1-13-5-summary-of-
manufacturing-changes>
) Summary of <m1-13-6-summary-of-
microbiological changes microbiological-changes>
<leaf>
</leaf>
</m1-13-6-summary-of-
microbiological-changes
<m1-13-7-summary-other-
) Summary of Other
significant-new-information>
Significant New
Information <leaf>
</leaf>
</m1-13-7-summary-other-
significant-new-information>
<m1-13-8-individual-study-
) Individual Study
information>
Information
<leaf>
</leaf>
</m1-13-8-individual-study-
information>
Version 1.3 19

for clarity)
<m1-13-9-general-investigational-
) General Investigational
plan>
Plan
<leaf>
</leaf>
</m1-13-9-general-investigational-
plan>
<m1-13-10-foreign-marketing-
) Foreign Marketing
history>
History
<leaf>
</leaf>
</m1-13-10-foreign-marketing-
history>
<m1-13-11-distribution-data>
) Distribution Data
<leaf>
</leaf>
</m1-13-11-distribution-data>
<m1-13-12-status-postmarketing-
) Status of Postmarketing
study-commitments>
Study Commitments
<leaf>
</leaf>
</m1-13-12-status-postmarketing-
study-commitments>
<m1-13-13-status-other-
) Status of Other
postmarketing-studies>
Postmarketing Studies
<leaf>
</leaf>
</m1-13-13-status-other-
postmarketing-studies>
<m1-13-14-log-outstanding-
) Log of Outstanding
regulatory-business>
Regulatory Business
<leaf>
</leaf>
</m1-13-14-log-outstanding-
regulatory-business>
End Annual Report </m1-13-annual-report>
0. Labeling <m1-14-labeling>
<m1-14-1-draft-labeling>
) Draft Labeling
<leaf>
</leaf>
</m1-14-1-draft-labeling>
Version 1.3 20

for clarity)
<m1-14-1-1-draft-carton-
(0) Draft Carton and Container Labels container-labels>
<leaf>
</leaf>
</m1-14-1-1-draft-carton-
container-labels>
<m1-14-1-2-annotated-draft-
(0) Annotated Draft Labeling Text labeling-text>
<leaf>
</leaf>
</m1-14-1-2-annotated-draft-
labeling-text>
<m1-14-1-3-draft-labeling-text>
(0) Draft Labeling Text <leaf>
</leaf>
</m1-14-1-3-draft-labeling-text>
<m1-14-1-4-label-comprehension-
(0) Label Comprehension Studies studies>
<leaf>
</leaf>
</m1-14-1-4-label-comprehension-
studies>
<m1-14-1-5-labeling-history>
(0) Labeling History <leaf>
</leaf>
</m1-14-1-5-labeling-history>
<m1-14-2-final-labeling>
) Final Labeling
</m1-14-2-final-labeling>
<m1-14-2-1-final-carton-container-
(0) Final Carton or Container Labels labels>
<leaf>
</leaf>
</m1-14-2-1-final-carton-
container-labels>
<m1-14-2-2-final-package-insert-
(0) Final Package Insert (package package-inserts>
inserts, patient information, medication <leaf>
guides) </leaf>
</m1-14-2-2-final-package-insert-
package-inserts>
<m1-14-2-3-final-labeling-text>
(0) Final labeling Text <leaf>
</leaf>
</m1-14-2-3-final-labeling-text>
Version 1.3 21

for clarity)
<m1-14-3-listed-drug-labeling>
) Listed Drug Labeling
<leaf>
</leaf>
</m1-14-3-listed-drug-labeling>
<m1-14-3-1-annotated-
(0) Annotated Comparison with Listed comparison-listed-drug>
Drug <leaf>
</leaf>
</m1-14-3-1-annotated-
comparison-listed-drug>
<m1-14-3-2-approved-labeling-
(0) Approved Labeling Text for Listed text-listed-drug>
Drug <leaf>
</leaf>
</m1-14-3-2-approved-labeling-
text-listed-drug>
<m1-14-3-3-labeling-text-
(0) Labeling Text for Reference Listed reference-listed-drug>
Drug <leaf>
</leaf>
</m1-14-3-3-labeling-text-
reference-listed-drug>
<m1-14-4-investigational-drug-
) Investigational Drug
labeling>
Labeling
<leaf>
</leaf>
</m1-14-4-investigational-drug-
labeling>
<m1-14-4-1-investigational-
(0) Investigational Brochure brochure>
<leaf>
</leaf>
</m1-14-4-1-investigational-
brochure>
<m1-14-4-2-investigational-drug-
(0) Investigational Drug Labeling label>
<leaf>
</leaf>
</m1-14-4-2-investigational-drug-
label>
<m1-14-5-foreign-labeling>
) Foreign Labeling
<leaf>
</leaf>
</m1-14-5-foreign-labeling>
Version 1.3 22

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)




<!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"
>

<!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
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
Version 1.3 23

>
<!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
xlink:title CDATA #REQUIRED
xlink:href CDATA #REQUIRED
>
<!ELEMENT node-extension (title, (leaf | node-extension)+)>
<!ATTLIST node-extension
ID ID #IMPLIED
>

<!ATTLIST date
>
<!ATTLIST prod-name
>

<!ELEMENT application-information (submission)>
<!ATTLIST application-information
Version 1.3 24
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)>

<!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;
>

<!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?)>
Version 1.3 25
<!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;
>
%att;
>
%att;
>
%att;
>
%att;
>

<!ELEMENT m1-2-cover-letters ((leaf | node-extension)*)>
<!ATTLIST m1-2-cover-letters
%att;
>

<!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*,
Version 1.3 26
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
<!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;
>

<!ELEMENT m1-3-2-field-copy-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-2-field-copy-certification
%att;
>

<!ELEMENT m1-3-3-debarment-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-3-debarment-certification
%att;
>

<!ELEMENT m1-3-4-financial-certification-disclosure ((leaf | node-extension)*)>
<!ATTLIST m1-3-4-financial-certification-disclosure
%att;
>

<!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
<!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;
>

<!ELEMENT m1-5-application-status (
m1-5-1-withdrawal-request*,
m1-5-2-inactivation-request*,
Version 1.3 28
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;
>

<!ELEMENT m1-6-meetings (m1-6-1-meeting-request*, m1-6-2-meeting-background-
materials*, 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;
>
Version 1.3 29
<!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;
>

<!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
<!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;
>

<!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)*)>
Version 1.3 30
<!ATTLIST m1-8-3-stability-study
%att;
>

<!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
<!ATTLIST m1-9-3-request-pediatric-exclusivity-determination
%att;
>
<!ELEMENT m1-9-4-proposed-pediatric-study-request-amendments
<!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
<!ATTLIST m1-9-6-other-correspondence-regarding-pediatric-exclusivity-study-plans
%att;
>

<!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
Version 1.3 31
%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;
>

<!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
<!ATTLIST m1-11-4-multiple-module-information-amendments
%att;
>

<!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*,
Version 1.3 32
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
<!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
<!ATTLIST m1-12-6-exemption-informed-consent-emergency-research
%att;
>
<!ELEMENT m1-12-7-public-disclosure-statement-emergency-care-research
<!ATTLIST m1-12-7-public-disclosure-statement-emergency-care-research
%att;
>
<!ELEMENT m1-12-8-correspondence-regarding-emergency-care-research
<!ATTLIST m1-12-8-correspondence-regarding-emergency-care-research
%att;
Version 1.3 33
>
<!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
<!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
<!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
<!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;
>

<!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*,
Version 1.3 34
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
<!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
<!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;
Version 1.3 35
>
<!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
<!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;
>

<!ELEMENT m1-15-promotional-material ((leaf | node-extension)*)>
<!ATTLIST m1-15-promotional-material
%att;
>

<!ELEMENT m1-16-risk-management-plans ((leaf | node-extension)*)>
<!ATTLIST m1-16-risk-management-plans
%att;
>
Version 1.3 38
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
Revision History
2004-03-11 1.1 Clarifications to the original version
I. START AND FINISH OF THE MODULE 2 TO 5 ECTD BACKBONE FILE.........................................3
II. LEAF ELEMENT ..............................................................................................................................................4

A. START TAG FOR THE LEAF ELEMENT................................................................................................................5
B. ID ATTRIBUTE FOR LEAF ELEMENT ..................................................................................................................5
C. OPERATION ATTRIBUTE FOR THE LEAF ELEMENT .............................................................................................6
D. MODIFIED-FILE ATTRIBUTE FOR THE LEAF ELEMENT ........................................................................................6
E. CHECKSUM ATTRIBUTE FOR THE LEAF ELEMENT ..............................................................................................7
F. CHECKSUM-TYPE ATTRIBUTE FOR THE LEAF ELEMENT .....................................................................................7
G. XLINK:HREF ATTRIBUTE FOR THE LEAF ELEMENT .............................................................................................8
H. XLINK:SHOW ATTRIBUTE ..................................................................................................................................8
I. TITLE CHILD ELEMENT OF THE LEAF ELEMENT .................................................................................................8
J. END TAG FOR THE LEAF ELEMENT ...................................................................................................................9
III. HEADING ELEMENT......................................................................................................................................9
A. HEADING ELEMENTS ATTRIBUTES FOR MODULE 2 .........................................................................................11
B. HEADING ELEMENTS AND ATTRIBUTES FOR MODULE 3..................................................................................14
C. HEADING ELEMENTS AND ATTRIBUTES FOR MODULE 4 ..................................................................................23
D. HEADING ELEMENTS AND ATTRIBUTES FOR MODULE 5 ..................................................................................28
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. 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 eCTD backbone files
4. Organization element and Leaf element for the Module 1 eCTD Backbone File
5. 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.
Version 1.1 3

</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 Purpose of leaf Element Part

<leaf> Tag indicating start of leaf element to organize the information for .
each submitted file.
ID This attribute provides a unique identification of the leaf element in
the submission.
operation This attribute provides information about the life cycle of the leaf.
modified-file This attribute provides the ID of a previously submitted leaf that is
effected by the operation attribute in the current submission, if
applicable .
checksum This attribute provides the document's checksum value (Also
known as document's "hash").
checksum-type 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.
xlink:href This attribute provides the location of the file using the file’s path.
xlink:show This attribute has not yet been defined within ICH
title 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).
</leaf> 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"
Version 1.1 4
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:
2
Including previously submitted information. See Guidance to Industry: Providing Regulatory
Submissions in Electronic Format — Human Drug Applications and Related Submissions for
more information.
Version 1.1 5
ID="a1234567"
ID=”id12235”
ID=”pid1234”
The following are invalid values for the ID attribute:
ID=”123a456” - does not start with a letter

ID=”1234567” - does not have a letter
ID=”a 1246” - 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 Meaning

operation ="new" This means that the leaf does not have an effect on a leaf included in
previously submitted eCTD backbone files.
operation ="append" 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.
operation ="replace" This means the file contained in the current leaf replaces a file
contained in a leaf in a previously submitted eCTD backbone file.
operation ="delete" 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
Version 1.1 6
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 file’s leaf element. You should append
the modified file’s 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-listing-
studies.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.
Version 1.1 7
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
Version 1.1 8
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-technical-
document-summaries contains the heading element m2-2-introduction. The heading element m2-
2-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>
Version 1.1 9
</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 Applicable Heading Element(s)

substance <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>
product-name <m3-2-p-drug-product>
dosageform <m3-2-p-drug-product>
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
Version 1.1 10
<m3-2-a-2-adventitious-agents-safety-evaluation> manufacturer
substance
dosageform
product-name
<m5-3-5-reports-of-efficacy-and-safety-studies> 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 heading element (leaf element abbreviated for clarity)
Module 2: Common Technical <m2-common-technical-document-summaries>
Document (CTD) Summaries
2.2 CTD Introduction <m2-2-introduction>
<leaf>
</leaf>
</m2-2-introduction>
Module 2: Quality Overall Summary <m2-3-quality-overall-summary>
(QOS) <leaf>
</leaf>
</m2-3-quality-overall-summary>
Module 2: Nonclinical Overview <m2-4-nonclinical-overview>
<leaf>
</leaf>
</m2-4-nonclinical-overview>
Module 2: Nonclinical Written and <m2-6-nonclinical-written-and-tabulated-summaries>
Version 1.1 11
Tabulated Summaries (NWTS)
2.6.1 Introduction <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-and-
Biopharmaceutic associated-analytical-methods>
Studies and Associated <leaf>
Analytical Methods </leaf>
</m2-7-1-summary-of-biopharmaceutic-studies-and-
associated-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="">
Version 1.1 12
<leaf>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>4
2.7.4 Summary of Clinical <m2-7-4-summary-of-clinical-safety>
Safety <leaf>
</leaf>
</m2-7-4-summary-of-clinical-safety>
2.7.5 References <m2-7-5-literature-references>
<leaf>
</leaf>
</m2-7-5-literature-references>
2.7.6 Synopses of Individual <m2-7-6-synopses-of-individual-studies>
Studies <leaf>
</leaf>
</m2-7-6-synopses-of-individual-studies>
End CS </m2-7-clinical-summary>
End CTD Summaries </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-of-
clinical-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:
<m2-7-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-clinical-summary>
4
See the description of element attributes after this table
5
Leaf element abbreviated for clarity.
6
Version 1.1 13
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
eCTD backbone file.
Module 3 CTD Heading eCTD Element

Module: 3 Quality <m3-quality>
3.2 Body of Data <m3-2-body-of-data>
3.2.S Drug Substance <m3-2-s-drug-substance
Name substance=""
Manufacturer manufacturer="">7
3.2.S.1 General Information <m3-2-s-1-general-information>
3.2.S.1.1 Nomenclature <m3-2-s-1-1-nomenclature>
<leaf>
</leaf>
</m3-2-s-1-1-nomenclature>
3.2.S.1.2 Structure <m3-2-s-1-2-structure>
<leaf>
</leaf>
</m3-2-s-1-2-structure>
3.2.S.1.3 General Properties <m3-2-s-1-3-general-properties>
<leaf>
</leaf>
</m3-2-s-1-3-general-properties>
End General Information </m3-2-s-1-general-information>
3.2.S.2 Manufacture <m3-2-s-2-manufacture>
7
See the description of element attributes after this table.
Version 1.1 14

3.2.S.2.1 Manufacturers <m3-2-s-2-1-manufacturer>
<leaf>
</leaf>
</m3-2-s-2-1-manufacturer>
3.2.S.2.2 Description of <m3-2-s-2-2-description-of-manufacturing-process-and-
Manufacturing process-controls>
<leaf>
</leaf>
</m3-2-s-2-2-description-of-manufacturing-process-and-
process-controls>
3.2.S.2.3 Control of Materials <m3-2-s-2-3-control-of-materials>
<leaf>
</leaf>
</m3-2-s-2-3-control-of-materials>
3.2.S.2.4 Controls of Critical <m3-2-s-2-4-controls-of-critical-steps-and-
Steps and Intermediates intermediates>
<leaf>
</leaf>
</m3-2-s-2-4-controls-of-critical-steps-and-
intermediates>
3.2.S.2.5 Process Validation <m3-2-s-2-5-process-validation-and-or-evaluation>
and/or Evaluation <leaf>
</leaf>
</m3-2-s-2-5-process-validation-and-or-evaluation>
3.2.S.2.6 Manufacturing Process <m3-2-s-2-6-manufacturing-process-development>
Development <leaf>
</leaf>
</m3-2-s-2-6-manufacturing-process-development>
End Manufacture </m3-2-s-2-manufacture>
3.2.S.3 Characterization <m3-2-s-3-characterisation>
3.2.S.3.1 Elucidation of Structure <m3-2-s-3-1-elucidation-of-structure-and-other-
and other Characteristics characteristics>
<leaf>
</leaf>
</m3-2-s-3-1-elucidation-of-structure-and-other-
characteristics>
3.2.S.3.2 Impurities <m3-2-s-3-2-impurities>
<leaf>
</leaf>
</m3-2-s-3-2-impurities>
End Characterization </m3-2-s-3-characterisation>
3.2.S.4 Control of Drug Substance <m3-2-s-4-control-of-drug-substance>
Version 1.1 15

3.2.S.4.1 Specification <m3-2-s-4-1-specification>
<leaf>
</leaf>
</m3-2-s-4-1-specification>
3.2.S.4.2 Analytical Procedures <m3-2-s-4-2-analytical-procedures>
<leaf>
</leaf>
</m3-2-s-4-2-analytical-procedures>
3.2.S.4.3 Validation of Analytical <m3-2-s-4-3-validation-of-analytical-procedures>
Procedures <leaf>
</leaf>
</m3-2-s-4-3-validation-of-analytical-procedures>
3.2.S.4.4 Batch Analyses <m3-2-s-4-4-batch-analyses>
<leaf>
</leaf>
</m3-2-s-4-4-batch-analyses>
3.2.S.4.5 Justification of <m3-2-s-4-5-justification-of-specification>
Specification <leaf>
</leaf>
</m3-2-s-4-5-justification-of-specification>
End Control of Drug Substance </m3-2-s-4-control-of-drug-substance>
3.2.S.5 Reference Standards or <m3-2-s-5-reference-standards-or-materials>
Materials <leaf>
</leaf>
</m3-2-s-5-reference-standards-or-materials>
3.2.S.6 Container Closure System <m3-2-s-6-container-closure-system>
<leaf>
</leaf>
</m3-2-s-6-container-closure-system>
3.2.S.7 Stability <m3-2-s-7-stability>
3.2.S.7.1 Stability Summary and <m3-2-s-7-1-stability-summary-and-conclusions>
Conclusions <leaf>
</leaf>
</m3-2-s-7-1-stability-summary-and-conclusions>
3.2.S.7.2 Postapproval Stability <m3-2-s-7-2-post-approval-stability-protocol-and-
Protocol and Stability stability-commitment>
Commitment <leaf>
</leaf>
</m3-2-s-7-2-post-approval-stability-protocol-and-
stability-commitment>
3.2.S.7.3 Stability Data <m3-2-s-7-3-stability-data>
<leaf>
</leaf>
</m3-2-s-7-3-stability-data>
End Stability </m3-2-s-7-stability>
Version 1.1 16

End Drug Substance </m3-2-s-drug-substance>
3.2.P Drug Product <m3-2-p-drug-product
Name product-name=""
Dosage Form dosageform=""
Manufacturer manufacturer="">8
3.2.P.1 Description and Composition<m3-2-p-1-description-and-composition-of-the-drug-
of the Drug Product product>
</m3-2-p-1-description-and-composition-of-the-drug-
product>
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-and-
Manufacturing Process and process-controls>
Process Controls <leaf>
</leaf>
</m3-2-p-3-3-description-of-manufacturing-process-and-
process-controls>
3.2.P.3.4 Controls of Critical <m3-2-p-3-4-controls-of-critical-steps-and-
Steps and Intermediates intermediates>
<leaf>
</leaf>
</m3-2-p-3-4-controls-of-critical-steps-and-
intermediates>
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
Version 1.1 17

3.2.P.4.1 Specifications <m3-2-p-4-1-specifications>
<leaf>
</leaf>
</m3-2-p-4-1-specifications>
3.2.P.4.2 Analytical Procedures <m3-2-p-4-2-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-4-2-analytical-procedures>
3.2.P.4.3 Validation of Analytical <m3-2-p-4-3-validation-of-analytical-procedures>
Procedures <leaf>
</leaf>
</m3-2-p-4-3-validation-of-analytical-procedures>
3.2.P.4.4 Justification of <m3-2-p-4-4-justification-of-specifications>
Specifications <leaf>
</leaf>
</m3-2-p-4-4-justification-of-specifications>
3.2.P.4.5 Excipients of Human or <m3-2-p-4-5-excipients-of-human-or-animal-origin>
Animal Origin <leaf>
</leaf>
</m3-2-p-4-5-excipients-of-human-or-animal-origin>
3.2.P.4.6 Novel Excipients <m3-2-p-4-6-novel-excipients>
<leaf>
</leaf>
</m3-2-p-4-6-novel-excipients>
End Control of Excipients </m3-2-p-4-control-of-excipients>
3.2.P. 5 Control of Drug Product <m3-2-p-5-control-of-drug-product>
3.2.P.5.1 Specifications <m3-2-p-5-1-specifications>
<leaf>
</leaf>
3.2.P.5.2 Analytical Procedures <m3-2-p-5-2-analytical-procedures>
<leaf>
</leaf>
3.2.P.5.3 Validation of Analytical <m3-2-p-5-3-validation-of-analytical-procedures>
Procedures <leaf>
</leaf>
</m3-2-p-5-3-validation-of-analytical-procedures>
3.2.P.5.4 Batch Analyses <m3-2-p-5-4-batch-analyses>
<leaf>
</leaf>
</m3-2-p-5-4-batch-analyses>
Version 1.1 18

3.2.P.5.5 Characterization of <m3-2-p-5-5-characterisation-of-impurities>
Impurities <leaf>
</leaf>
</m3-2-p-5-5-characterisation-of-impurities>
3.2.P.5.6 Justification of <m3-2-p-5-6-justification-of-specifications>
Specifications <leaf>
</leaf>
End Control of Drug Product </m3-2-p-5-control-of-drug-product>
3.2.P.6 Reference Standards or <m3-2-p-6-reference-standards-or-materials>
Materials <leaf>
</leaf>
</m3-2-p-6-reference-standards-or-materials>
3.2.P.7 Container Closure System <m3-2-p-7-container-closure-system>
<leaf>
</leaf>
</m3-2-p-7-container-closure-system>
3.2.P.8 Stability <m3-2-p-8-stability>
3.2.P.8.1 Stability Summary and <m3-2-p-8-1-stability-summary-and-conclusion>
Conclusion <leaf>
</leaf>
</m3-2-p-8-1-stability-summary-and-conclusion>
3.2.P.8.2 Postapproval Stability <m3-2-p-8-2-post-approval-stability-protocol-and-
Protocol and Stability stability-commitment>
Commitment <leaf>
</leaf>
</m3-2-p-8-2-post-approval-stability-protocol-and-
stability-commitment>
3.2.P.8.3 Stability Data <m3-2-p-8-3-stability-data>
<leaf>
</leaf>
</m3-2-p-8-3-stability-data>
End Stability </m3-2-p-8-stability>
End Drug Product </m3-2-p-drug-product>
3.2.A APPENDICES <m3-2-a-appendices>
3.2.A.1 Facilities and Equipment <m3-2-a-1-facilities-and-equipment
manufacturer=""
substance=""
dosageform=""
product-name="">10
<leaf>
</leaf>
</m3-2-a-1-facilities-and-equipment
10
Version 1.1 19

3.2.A.2 Adventitious Agents <m3-2-a-2-adventitious-agents-safety-evaluation
Safety Evaluation manufacturer=""
substance=""
dosageform=""
product-name="">11
<leaf>
</leaf>
</m3-2-a-2-adventitious-agents-safety-evaluation>
3.2.A.3 Novel Excipients <m3-2-a-3-excipients>
<leaf>
</leaf>
</m3-2-a-3-excipients>
End Appendices </m3-2-a-appendices>
3.2.R REGIONAL INFORMATION <m3-2-r-regional-information>
<leaf>
</leaf>
</m3-2-r-regional-information>
End Body of Data </m3-2-body-of-data>
3.3 LITERATURE REFERENCES <m3-3-literature-references>
<leaf>
</leaf>
</m3-3-literature-references>
End Quality </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
Version 1.1 20
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-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 >
manufacturer="Puerto Rico Internal-Plant-#2">
<leaf></leaf>15
</m3-2-p-drug-product>
</ m3-2-body-of-data >
</m3-quality >
12
13
14
15
Version 1.1 21
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>
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-4-2-analytical-procedures>
<leaf></leaf>17
<m3-2-p-4-4-justification-of-specifications>
<leaf></leaf>18
</m3-2-p-4-control-of-excipients>
</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-and-
equipment> and for the Adventitious Agents Safety Evaluation heading, <m3-2-a-2-
16
17
18
Version 1.1 22
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
19
20
Version 1.1 23
eCTD backbone file.

Module 4: Nonclinical Study Reports <m4-nonclinical-study-reports>
4.2 Study Reports <m4-2-study-reports>
4.2.1 Pharmacology <m4-2-1-pharmacology>
4.2.1.1 Primary Pharmacodynamics <m4-2-1-1-primary-pharmacodynamics>
<leaf>
</leaf>
</m4-2-1-1-primary-pharmacodynamics>
4.2.1.2 Secondary <m4-2-1-2-secondary-pharmacodynamics>
Pharmacodynamics <leaf>
</leaf>
</m4-2-1-2-secondary-pharmacodynamics>
4.2.1.3 Safety Pharmacology <m4-2-1-3-safety-pharmacology>
<leaf>
</leaf>
</m4-2-1-3-safety-pharmacology>
4.2.1.4 Pharmacodynamic Drug <m4-2-1-4-pharmacodynamic-drug-interactions>
Interactions <leaf>
</leaf>
</m4-2-1-4-pharmacodynamic-drug-interactions>
End Pharmacology </m4-2-1-pharmacology>
4.2.2 Pharmacokinetics <m4-2-2-pharmacokinetics>
4.2.2.1 Analytical Methods and <m4-2-2-1-analytical-methods-and-validation-
Validation Reports reports>
<leaf>
</leaf>
</m4-2-2-1-analytical-methods-and-validation-
reports>
4.2.2.2 Absorption <m4-2-2-2-absorption>
<leaf>
</leaf>
</m4-2-2-2-absorption>
4.2.2.3 Distribution <m4-2-2-3-distribution>
<leaf>
</leaf>
</m4-2-2-3-distribution>
4.2.2.4 Metabolism <m4-2-2-4-metabolism>
<leaf>
</leaf>
</m4-2-2-4-metabolism>
Version 1.1 24

4.2.2.5 Excretion <m4-2-2-5-excretion>
<leaf>
</leaf>
</m4-2-2-5-excretion>
4.2.2.6 Pharmacokinetic Drug <m4-2-2-6-pharmacokinetic-drug-interactions>
Interactions <leaf>
</leaf>
</m4-2-2-6-pharmacokinetic-drug-interactions>
4.2.2.7 Other Pharmacokinetic <m4-2-2-7-other-pharmacokinetic-studies>
Studies <leaf>
</leaf>
</m4-2-2-7-other-pharmacokinetic-studies>
End Pharmacokinetics </m4-2-2-pharmacokinetics>
4.2.3 Toxicology <m4-2-3-toxicology>
4.2.3.1 Single-Dose Toxicity <m4-2-3-1-single-dose-toxicity>
<leaf>
</leaf>
</m4-2-3-1-single-dose-toxicity>
4.2.3.2 Repeat-Dose Toxicity <m4-2-3-2-repeat-dose-toxicity>
<leaf>
</leaf>
</m4-2-3-2-repeat-dose-toxicity>
4.2.3.3 Genotoxicity <m4-2-3-3-genotoxicity>
<leaf>
</leaf>
4.2.3.3.1 In vitro <m4-2-3-3-1-in-vitro>
<leaf>
</leaf>
</m4-2-3-3-1-in-vitro>
4.2.3.3.2 In vivo <m4-2-3-3-2-in-vivo>
<leaf>
</leaf>
</m4-2-3-3-2-in-vivo>
End Genotoxicity </m4-2-3-3-genotoxicity>
4.2.3.4 Carcinogenicity <m4-2-3-4-carcinogenicity>
4.2.3.4.1 Long-term studies <m4-2-3-4-1-long-term-studies>
<leaf>
</leaf>
</m4-2-3-4-1-long-term-studies>
4.2.3.4.2 Short- or medium-term <m4-2-3-4-2-short-or-medium-term-studies>
studies <leaf>
</leaf>
</m4-2-3-4-2-short-or-medium-term-studies>
Version 1.1 25

4.2.3.4.3 Other studies <m4-2-3-4-3-other-studies>
<leaf>
</leaf>
</m4-2-3-4-3-other-studies>
End Carcinogenicity </m4-2-3-4-carcinogenicity>
4.2.3.5 Reproductive and <m4-2-3-5-reproductive-and-developmental-
Developmental Toxicity toxicity>
4.2.3.5.1 Fertility and early <m4-2-3-5-1-fertility-and-early-embryonic-
embryonic development development>
<leaf>
</leaf>
</m4-2-3-5-1-fertility-and-early-embryonic-
development>
4.2.3.5.2 Embryofetal <m4-2-3-5-2-embryo-fetal-development>
development <leaf>
</leaf>
</m4-2-3-5-2-embryo-fetal-development>
4.2.3.5.3 Prenatal and postnatal <m4-2-3-5-3-prenatal-and-postnatal-
development, including maternal development-including-maternal-function>
function <leaf>
</leaf>
</m4-2-3-5-3-prenatal-and-postnatal-
development-including-maternal-function>
4.2.3.5.4 Studies in which the <m4-2-3-5-4-studies-in-which-the-offspring-
offspring juvenile-animals-are-dosed-and-or-further-
evaluated>
<leaf>
</leaf>
</m4-2-3-5-4-studies-in-which-the-offspring-
juvenile-animals-are-dosed-and-or-further-
evaluated>
End Reproductive Toxicology </m4-2-3-5-reproductive-and-developmental-
toxicity>
4.2.3.6. Local Tolerance <m4-2-3-6-local-tolerance>
<leaf>
</leaf>
</m4-2-3-6-local-tolerance>
4.2.3.7. Other Toxicity Studies <m4-2-3-7-other-toxicity-studies>
4.2.3.7.1 Antigenicity <m4-2-3-7-1-antigenicity>
<leaf>
</leaf>
</m4-2-3-7-1-antigenicity>
Version 1.1 26

4.2.3.7.2 Immunotoxicity <m4-2-3-7-2-immunotoxicity>
<leaf>
</leaf>
</m4-2-3-7-2-immunotoxicity>
4.2.3.7.3 Mechanistic studies <m4-2-3-7-3-mechanistic-studies>
<leaf>
</leaf>
</m4-2-3-7-3-mechanistic-studies>
4.2.3.7.4 Dependence <m4-2-3-7-4-dependence>
<leaf>
</leaf>
</m4-2-3-7-4-dependence>
4.2.3.7.5 Metabolites <m4-2-3-7-5-metabolites>
<leaf>
</leaf>
</m4-2-3-7-5-metabolites>
4.2.3.7.6 Impurities <m4-2-3-7-6-impurities>
<leaf>
</leaf>
</m4-2-3-7-6-impurities>
4.2.3.7.7 Other <m4-2-3-7-7-other>
<leaf>
</leaf>
</m4-2-3-7-7-other>
End Other </m4-2-3-7-other-toxicity-studies>
End Toxicology </m4-2-3-toxicology>
End Study Reports </m4-2-study-reports>
4.3 Literature References <m4-3-literature-references>
<leaf>
</leaf>
End Nonclinical </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
Version 1.1 27
</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
eCTD backbone file.

Module 5: Clinical Study Reports <m5-clinical-study-reports>
5.2 Tabular Listing Of All Clinical <m5-2-tabular-listing-of-all-clinical-studies>
Studies <leaf>
</leaf>
</m5-2-tabular-listing-of-all-clinical-studies>
5.3 Clinical Study Reports And <m5-3-clinical-study-reports>
Related Information
5.3.1 Reports Of Biopharmaceutic <m5-3-1-reports-of-biopharmaceutic-studies >
Studies
5.3.1.1 Bioavailability (BA) Study <m5-3-1-1-bioavailability-study-reports>
Reports <leaf>
</leaf>
</m5-3-1-1-bioavailability-study-reports>
Version 1.1 28

5.3.1.2 Comparative BA And <m5-3-1-2-comparative-ba-and-bioequivalence-
Bioequivalence (BE) Study Reports study-reports>
<leaf>
</leaf>
</m5-3-1-2-comparative-ba-and-bioequivalence-
study-reports>
5.3.1.3 In Vitro-In Vivo Correlation <m5-3-1-3-in-vitro-in-vivo-correlation-study-
Study Reports reports>
<leaf>
</leaf>
</m5-3-1-3-in-vitro-in-vivo-correlation-study-
reports>
5.3.1.4 Reports Of Bioanalytical And <m5-3-1-4-reports-of-bioanalytical-and-analytical-
Analytical Methods For Human methods-for-human-studies>
Studies <leaf>
</leaf>
</m5-3-1-4-reports-of-bioanalytical-and-analytical-
methods-for-human-studies>
End Biopharm </m5-3-1-reports-of-biopharmaceutic-studies>
5.3.2 Reports Of Studies Pertinent To <m5-3-2-reports-of-studies-pertinent-to-
Pharmacokinetics Using Human pharmacokinetics-using-human-biomaterials>
Biomaterials
5.3.2.1 Plasma Protein Binding Study <m5-3-2-1-plasma-protein-binding-study-reports>
Reports <leaf>
</leaf>
</m5-3-2-1-plasma-protein-binding-study-reports>
5.3.2.2 Reports Of Hepatic <m5-3-2-2-reports-of-hepatic-metabolism-and-drug-
Metabolism And Drug Interaction interaction-studies>
Studies <leaf>
</leaf>
</m5-3-2-2-reports-of-hepatic-metabolism-and-
drug-interaction-studies>
5.3.2.3 Reports Of Studies Using <m5-3-2-3-reports-of-studies-using-other-human-
Other Human Biomaterials biomaterials>
<leaf>
</leaf>
</m5-3-2-3-reports-of-studies-using-other-human-
biomaterials>
End Human Biomaterials </m5-3-2-reports-of-studies-pertinent-to-
pharmacokinetics-using-human-biomaterials>
5.3.3 Reports Of Human <m5-3-3-reports-of-human-pharmacokinetics-pk-
Pharmacokinetic (PK) Studies studies>
Version 1.1 29

5.3.3.1 Healthy Subject PK And Initial <m5-3-3-1-healthy-subject-pk-and-initial-
Tolerability Study Reports tolerability-study-reports>
<leaf>
</leaf>
</m5-3-3-1-healthy-subject-pk-and-initial-
tolerability-study-reports>
5.3.3.2 Patient PK And Initial <m5-3-3-2-patient-pk-and-initial-tolerability-study-
Tolerability Study Reports reports>
<leaf>
</leaf>
</m5-3-3-2-patient-pk-and-initial-tolerability-study-
reports>
5.3.3.3 Intrinsic Factor Pk Study <m5-3-3-3-intrinsic-factor-pk-study-reports>
Reports <leaf>
</leaf>
</m5-3-3-3-intrinsic-factor-pk-study-reports>
5.3.3.4 Extrinsic Factor Pk Study <m5-3-3-4-extrinsic-factor-pk-study-reports>
Reports <leaf>
</leaf>
</m5-3-3-4-extrinsic-factor-pk-study-reports>
5.3.3.5 Population Pk Study Reports <m5-3-3-5-population-pk-study-reports>
<leaf>
</leaf>
</m5-3-3-5-population-pk-study-reports>
End PK </m5-3-3-reports-of-human-pharmacokinetics-pk-
studies>
5.3.4 Reports Of Human <m5-3-4-reports-of-human-pharmacodynamics-pd-
Pharmacodynamic (PD) Studies studies>
5.3.4.1 Healthy Subject PD And <m5-3-4-1-healthy-subject-pd-and-pk-pd-study-
PK/PD Study Reports reports>
<leaf>
</leaf>
</m5-3-4-1-healthy-subject-pd-and-pk-pd-study-
reports>
5.3.4.2 Patient PD And PK/PD Study <m5-3-4-2-patient-pd-and-pk-pd-study-reports>
Reports <leaf>
</leaf>
</m5-3-4-2-patient-pd-and-pk-pd-study-reports>
</m5-3-4-reports-of-human-pharmacodynamics-pd-
studies>
5.3.5 Reports Of Efficacy And Safety <m5-3-5-reports-of-efficacy-and-safety-studies
Studies indication="">22
22
Version 1.1 30

5.3.5.1 Study Reports Of Controlled <m5-3-5-1-study-reports-of-controlled-clinical-
Clinical Studies Pertinent To The studies-pertinent-to-the-claimed-indication>
Claimed Indication <leaf>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinical-
studies-pertinent-to-the-claimed-indication>
5.3.5.2 Study Reports Of Uncontrolled <m5-3-5-2-study-reports-of-uncontrolled-clinical-
Clinical Studies studies>
<leaf>
</leaf>
</m5-3-5-2-study-reports-of-uncontrolled-clinical-
studies>
5.3.5.3 Reports Of Analyses Of Data <m5-3-5-3-reports-of-analyses-of-data-from-more-
From More Than One Study than-one-study>
<leaf>
</leaf>
</m5-3-5-3-reports-of-analyses-of-data-from-more-
than-one-study>
5.3.5.4 Other Study Reports <m5-3-5-4-other-study-reports>
<leaf>
</leaf>
</m5-3-5-4-other-study-reports>
End Efficacy and Safety </m5-3-5-reports-of-efficacy-and-safety-studies>
5.3.6 Reports Of Postmarketing <m5-3-6-reports-of-postmarketing-experience>
Experience <leaf>
</leaf>
</m5-3-6-reports-of-postmarketing-experience>
5.3.7 Case Report Forms and This heading is not used. The leaf for case report forms
Individual Patient Listings and individual patient listings files are placed with the
appropriate study report using the Study Tagging File
5.4literature References <m5-4-literature-references>
<leaf>
</leaf>
End Module 5 <m5-clinical-study-reports>
2. Attribute for Module 5 heading elements
The heading element for the Reports of Efficacy And Safety Studies (ES) heading, <m5-3-5-
reports-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.
Version 1.1 31
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
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
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 valid-
values.xml.
2005-07-25 2.6 Posting for FDA. Removed Cumulative Approach for STF Lifecycle
and added US regional name attribute value “individual-subject-data-
listing”. Also reinstituted "nonclinical-data" as US specific tag and
marked "pre-clinical-study-reports" as not used in US.
Page 1
THE SPECIFICATION FOR STUDY TAGGING FILES (STF) .........................................3

I. ST ART AND STOP OF THE STF..................................................................................3
II. ST UDY-IDENTIFIER ELEMENT ..................................................................................4
A. Title Element..........................................................................................................4
B. study-id Element.....................................................................................................4
C. Category Element ...................................................................................................4
III. STUDY-DOCUMENT AND DOC-CONTENT ELEMENTS..............................................6
A. Property element ....................................................................................................6
B. File-tag element .....................................................................................................6
IV. LIFECYCLE MANAGEMENT OF THE STUDY T AGGING FILE ....................................... 10
V. MODIFYING STF INFORMATION ..................................................................... 10
A. Changes to the STF Study Identifier Information .................................................... 11
B. Changes to STF Study Document Information ........................................................ 12
VI. STUDY DATA MANAGEMENT OPTIONS ......................................................... 16
A. Distinguishing Time-Specific Analyses Within the Same Subsection of the CTD........ 17
B. Presenting Information from One Study in a Different Subsection of the CTD .......... 17
VII. EXAMPLE SCENARIO .......................................................................................... 18
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 STF’s 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.
Page 3
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-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">

</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 study-
document.
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.
Page 4
•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 values for "category" element

Attributes and Values content choices
name="species"
info-type="ich" mouse
info-type="ich" rat
info-type="ich" hamster
info-type="ich" other-rodent
info-type="ich" rabbit
info-type="ich" dog
info-type="ich" non-human-primate
info-type="ich" other-non-rodent-mammal
info-type="ich" non-mammals
name="route-of-admin"
info-type="ich" oral
info-type="ich" intravenous
info-type="ich" intramuscular
info-type="ich" intraperitoneal
info-type="ich" subcutaneous
info-type="ich" inhalation
info-type="ich" topical
info-type="ich" other (1see footnote)
name="duration"
info-type="us" short
info-type="us" medium
info-type="us" long
name="type-of-control"
info-type="ich" placebo
info-type="ich" no-treatment
info-type="ich" dose-response-without-placebo
1
Please consult the regional authorities before using "other".
Page 5
Category Element values for "category" element

info-type="ich" active-control-without-placebo
info-type="ich" 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 values for "property" element

name="site-identifier" User identified value for the site of the
info-type="us" study.
B. File-tag element
The file-tag element contains the attributes name and info-type. The text value of the file-
tag 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
2
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.
Page 6
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 info- E3

for the file-tag element type Content of Document Reference
(name=" ") value
pre-clinical-study-report ich Pre-clinical study report ( 3see footnote)
NOTE: Do not use in STF submitted
to FDA4
legacy-clinical-study- ich Clinical study report submitted as one
report file (*see footnote)
synopsis ich Study Report Synopsis 2
study-report-body ich Study Report Body 1,3 to 15
protocol-or-amendment ich Protocol and/amendments 16.1.1
sample-case-report-form ich Sample CRF 16.1.2
iec-irb-consent-form-list ich IEC and IRB and Consent Form 16.1.3
Listings
list-description- ich 16.1.4
investigator-site Description of Investigators and Sites
signatures-investigators ich Signatures of principal or coordinating 16.1.5

investigator(s) or sponsor’s responsible
officer
list-patients-with- ich 16.1.6
Listing of patients receiving test
batches
drug(s) from specified batch
randomisation-scheme ich Randomisation Scheme 16.1.7
audit-certificates-report ich Audit Certificates or similar 16.1.8
documentation
statistical-methods- ich Documentation of statistical methods 16.1.9
interim-analysis-plan and interim analysis plans
inter-laboratory- ich 16.1.10
standardisation- Documentation of Inter-laboratory
methods-quality- Standardization Methods and Quality
assurance Assurance or similar documentation
3
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
Page 7

(name=" ") value
publications-based-on- ich 16.1.11
study Publications Based on the Study
publications-referenced- ich Publications Referenced in the Study 16.1.12

in-report Report
discontinued-patients ich Discontinued Patients Listing 16.2.1
protocol-deviations ich 16.2.2
Protocol Deviation Listing
patients-excluded-from- ich Patients Excluded from Efficacy 16.2.3
efficacy-analysis Analysis Listing
demographic-data ich Demographic Data Listing 16.2.4
compliance-and-drug- ich Compliance and/or Drug Concentration 16.2.5
concentration-data Data Listing
individual-efficacy- ich Individual Efficacy Response Data 16.2.6
response-data Listing
adverse-event-listings ich File contains Adverse Event Listings 16.2.7
listing-individual- ich 16.2.8
laboratory- Individual Laboratory Measurements
measurements-by- Listed by Patient
patient
case-report-forms ich CRF for an individual subject. If you 16.3
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.
available-on-request ich A file listing documents available upon
request for a single study. Consult
regional guidance for use.
complete-patient-list jp Complete patient list (Not used in STF
files submitted to FDA)
serious-adverse-event- jp List of patients having serious adverse
patient-list events (Not used in STF files
submitted to FDA)
adverse-event-patient- jp List of patients having adverse events
list (Not used in STF files submitted to
FDA)
abnormal-lab-values- jp List of patients having abnormal lab
patient-list values (Not used in STF files submitted
to FDA)
data-tabulation-dataset us Data tabulation dataset
Page 8

(name=" ") value
data-tabulation-data- us Data definitions for data tabulation
definition datasets
data-listing-dataset us Data listing dataset
data-listing-data- us
Data definitions for data listing datasets
definition
analysis-dataset us Analysis datasets
analysis-program us Program file for analysis dataset
analysis-data-definition us Data definition for analysis datasets
annotated-crf us Annotated CRF for datasets
ecg us Annotated ECG waveform dataset
image us Image files
subject-profiles us Subject profile. 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.
safety-report us IND safety report
antibacterial us Antibacterial microbiology report
special-pathogen us Special pathogens (e.g., fungi,
parasites, mycobacteria) and immune
modulator microbiology report
antiviral us Antiviral microbiology report
iss us Integrated analysis of safety –
integrated summary of safety report
ise us Integrated analysis of efficacy –
integrated summary of efficacy report
pm-description us Postmarketing periodic adverse event
drug experience report description
individual-subject-data- us
Individual-subject-data-listing
listing
nonclinical-data 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.
Page 9
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
Page 10
• 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:
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
Page 11
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:
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-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>
<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
Page 12
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
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
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 pre-
existing STFs for the study but these files will no longer show as ‘current’ because they
have been replaced in the backbone of the application.
Page 13
3. Deleting Files Cited by an Existing STF
Cumulative 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
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 legacy-
clinical-study-report in submission serial 0000 and corrects the error in submission 0003.
In the serial 0000 index.xml,
Page 14
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>
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"
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:
xlink:href="../0000/m4/42-stud-rep/423-tox/4231-single-dose-tox/synopsis-of-jm-12-
345.pdf"
<title>jm-12-345 Study Synopsis</title>
ID="r34567">
</leaf>
Page 15
Finally, include a new STF (using the "append" operation) and associate the correct
synopsis file-tag to the file.
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-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet.xsl"?>
<study-identifier>
<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
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
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-claimed-
indication>
xlink:href="m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-rep-
contr/study-s107/synopsis.pdf"
ID="a101">
<title>S107 Study Synopsis - Interim Results</title>
</leaf>
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="new"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-rep-
contr/study-s107/study-report-body.pdf"
ID="a102">
<title>S107 Study Report Body - Interim Results</title>
</leaf>
Page 18
checksum="98723f7594b5500a861509547c384e46" operation="new"
contr/study-s107/protocol.pdf"
ID="a103">
<title>S107 Study Protocol</title>
</leaf>
checksum="25d3b246313a9dbf688a48da2295260e" operation="new"
contr/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-claimed-
indication>
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-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet-2-2.xsl"?>
<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">
</doc-content>
<file-tag name="study-report-body" info-type="ich"/>
</doc-content>
<file-tag name="protocol-or-amendment” info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
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
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
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:
indication>
contr/study-s107/protamend01.pdf"
ID="a567">
<title>S107 Protocol Amendment No. 1</title>
</leaf>
contr/study-s107/samplecrf.pdf"
ID="a568">
<title>S107 Sample Case Report Form</title>
</leaf>
checksum="25d3b246313a9dbf688a48da2295260e" operation="append"
modified-file="../0000/index.xml#a104"
ID="a569">
Page 20

</leaf>
indication>
The new STF is also named "stf-s107.xml" and summarizes only the new information
being provided in this submission as follows:

<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-2-2stylesheet.xsl"?>
<study-identifier>
<category name="type-of-control" info-type="ich">no-treatment</category>
</study-identifier>
<study-document>
<file-tag name="protocol-or-amendment" info-type="ich"/>
</doc-content>
<file-tag name="sample-case-report-form" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
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
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
indication>
checksum="421e55366d62fad0e9510f6aed005272" operation="replace"
contr/study-s107/synopsis.pdf"
ID="r345">
<title>S107 Study Synopsis - Final</title>
</leaf>
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="replace"
contr/study-s107/s107body.pdf"
ID="r346">
<title>S107 Study Report - Final</title>
</leaf>
contr/study-s107/crf/11/12.pdf"
ID="r347">
<title>CRF for Subject S107-11-12</title>
</leaf>
contr/study-s107/crf/162/5045.pdf"
ID="r348">
<title>CRF for Patient S107-162-5045</title>
</leaf>
checksum="25d3b246313a9dbf688a48da2295260e" operation="append"
ID="r349">
</leaf>
Page 22
indication>
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-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet-2-2.xsl"?>
<study-identifier>
<category name="type-of-control" info-type="ich">placebo</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#r345">
</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>
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

Version Date Description
Number
Version 1.0 Initial Baseline
Version 1.1 December 2002 Teleconference review of required
section
Version 1.2 January 2003 Revised by subsection of M2 EWG
Version 1.3 January 2003 Comments from subset of M2
members
Version 1.4 February 2003 ICH Tokyo M2 Meeting
Version 1.5 July 15, 2003 ICH Brussels M2 Meeting
Version 1.6 July 17, 2003 ICH Brussels M2 Meeting
Version 1.7 July 18, 2003 ICH Brussels M2 Meeting – FDA
Lawyer Comments
Version 1.8 June 10, 2004 ICH Tyson’s Corner Meeting – Add
release schedules
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
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 authority’s
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 party’s vote on eCTD change control
• Assigning regional members to present change requests originating in their region as
needed
1
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.
2
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
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.
4
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.
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 This should be a short summary of the problem submitted including
rationale.
Submit Date Date you submit the change request (YYYY-MM-DD)
Item to be Reference to the area of the specification to be changed (e.g., the eCTD
Changed/ Question DTD, the written specification, the M2 eCTD style sheet)
Version Number Indicate the specific version and date of the eCTD Specification for
and Date which the change is proposed.
Description 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.
Document Change History

Version Date Description
Number
Version 3.0 October 2003 Initial Step 4 Document
Version 3.1 November 2003 Incorporate approved change requests
00020, 00030, 00090, 00110, 00190,
00200, 00240, 00260, 00290, 00310,
00380, 00400, 00420, 00450, 00480,
00500, 00510, 00520, 00530
Version 3.2 February 2004 Editorial Corrections and Change to
Align with the M4 Organisation
Document : Granularity Annex
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
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
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:
• 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
Page 1
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 self-
contained 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 PDF
hello.rtf RTF
The mapping between formats and extensions are:
IANA nomenclature
text/css css
text/html html or htm
text/xml xml
application/pdf pdf
application/rtf rtf
application/vnd.ms-excel xls
image/jpeg jpg
image/png png
image/gif gif
Non IANA nomenclature

DTD dtd
XPT (SAS) xpt
XSL 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 applicant’s 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.
1
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 Description Folder Name
CTD
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 26-nonclin-sum

Summaries
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
CTD
Page 3-2
CTD
3.2 Body of Data 32-body-data
3.2.S Drug Substance 32s-drug-sub
3.2.S Drug Substance [Drug Substance Name] substance-1-manufacturer-1

[Manufacturer]2
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 Control of Drug Substance (name, 32s4-contr-drug-sub

manufacturer)
3.2.S.4.1 Specification (name, manufacturer) 32s41-spec
3.2.S.4.2 Analytical Procedures (name, manufacturer) 32s42- analyt-proc
3.2.S.4.3 Validation of Analytical Procedures (name, 32s43-val-analyt-proc

manufacturer)
3.2.S.4.4 Batch Analyses (name, manufacturer) 32s44-batch-analys
3.2.S.4.5 Justification of Specification (name, 32s45-justif-spec

manufacturer)
3.2.S.5 Reference Standards or Materials (name, 32s5-ref-stand
manufacturer)
3.2.S.6 Container Closure System (name, 32s6-cont-closure-sys
manufacturer)
3.2.S.7 Stability (name, manufacturer) 32s7-stab
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 Description and Composition of the Drug 32p1-desc-comp

Product (name, dosage form)
3.2.P.2 Pharmaceutical Development (name, dosage 32p2-pharm-dev
form)
3.2.P.3 Manufacture (name, dosage form) 32p3-manuf
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

Excipient 1
3.2.P.5 Control of Drug Product (name, dosage form) 32p5-contr-drug-prod
2
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
CTD
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, 32p53-val-analyt-proc

dosage form)
3.2.P.5.4 Batch Analyses (name, dosage form) 32p54-batch-analys
3.2.P.5.5 Characterisation of Impurities (name, dosage 32p55-charac-imp

form)
3.2.P.5.6 Justification of Specifications (name, dosage 32p56-justif-spec
form)
3.2.P.6 Reference Standards or Materials (name, dosage 32p6-ref-stand
form)
3.2.P.7 Container Closure System (name, dosage form) 32p7-cont-closure-sys
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 Adventitious Agents Safety Evaluation (name, 32a2-advent-agent

dosage form, manufacturer)
3.2.A.3 Excipients- Name 4 32a3-excip-name-1
3.2.R Regional Information5 32r-reg-info
3.3 Literature References 33-lit-ref
4
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
Module 4 Nonclinical Study Reports

Table 3-4
Section in
Description Folder Name
CTD
4.2 Study Reports 42-stud-rep
Page 3-5
Section in
CTD
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

Analytical Methods and Validation Reports (if
4.2.2.1 4221-analyt-met-val
separate reports are available)
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

Single-Dose Toxicity (in order by species, by
4.2.3.1 4231-single-dose-tox
route)
Repeat-Dose Toxicity (in order by species, by
4.2.3.2 route, by duration, including supportive 4232-repeat-dose-tox
toxicokinetics evaluations)
4.2.3.3 Genotoxicity 4233-genotox
4.2.3.3.1 In vitro 42331-in-vitro

In vivo (including supportive toxicokinetics
4.2.3.3.2 42332-in-vivo
evaluations)
Carcinogenicity (including supportive
4.2.3.4 4234-carcigen
toxicokinetics evaluations)
Long-term studies (in order by species,
including range-finding studies that cannot be
4.2.3.4.1 42341-lt-stud
appropriately included under repeat-dose
toxicity or pharmacokinetics)
Short-or medium-term studies (including range-
finding studies that cannot be appropriately
4.2.3.4.2 42342-smt-stud
included under repeat-dose toxicity or
pharmacokinetics)
Page 3-6
Section in
CTD
4.2.3.4.3 Other studies 42343-other-stud
Reproductive and Developmental Toxicity

(including range-finding studies and supportive
4.2.3.5 toxicokinetics evaluations)(If modified study 4235-repro-dev-tox
designs are used, the following subheadings
should be modified accordingly)
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

Prenatal and postnatal development, including
4.2.3.5.3 42353-pre-postnatal-dev
maternal function
Studies in which the offspring (juvenile
4.2.3.5.4 42354-juv
animals) are dosed and/or further evaluated
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
Page 3-7
Module 5 Clinical Study Reports

Table 3-5
Section in
CTD
5.2 Tabular Listing of all Clinical Studies 52-tab-list
Page 3-8
Section in
CTD
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

Comparative BA and Bioequivalence (BE)
5.3.1.2 5312-compar-ba-be-stud-rep
Study Reports
5.3.1.3 In vitro – In vivo Correlation Study Reports 5313-in-vitro-in-vivo-corr-stud-rep

Reports of Bioanalytical and Analytical
5.3.1.4 5314-bioanalyt-analyt-met
Methods for Human Studies

Reports of Studies Pertinent to
5.3.2 532-rep-stud-pk-human-biomat
Pharmacokinetics using Human Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports 5321-plasma-prot-bind-stud-rep

Reports of Hepatic Metabolism and Drug
5.3.2.2 5322-rep-hep-metab-interact-stud
Interaction Studies
Page 3-9
Section in
CTD
Reports of Studies Using Other Human

5.3.2.3 5323-stud-other-human-biomat
Biomaterials

Reports of Human Pharmacokinetic (PK)
5.3.3 533-rep-human-pk-stud
Studies
Healthy Subject PK and Initial Tolerability
5.3.3.1 5331-healthy-subj-pk-init-tol-stud-rep
Study Reports
Patient PK and Initial Tolerability Study

5.3.3.2 5332-patient-pk-init-tol-stud-rep
Reports
5.3.3.3 Intrinsic Factor PK Study Reports 5333-intrin-factor-pk-stud-rep
5.3.3.4 Extrinsic Factor PK Study Reports 5334-extrin-factor-pk-stud-rep
5.3.3.5 Population PK Study Reports 5335-popul-pk-stud-rep
Page 3-10
Section in
CTD
Reports of Human Pharmacodynamic (PD)

5.3.4 534-rep-human-pd-stud
Studies
5.3.4.1 Healthy Subject PD and PK/PD Study Reports 5341-healthy-subj-pd-stud-rep
5.3.4.2 Patient PD and PK/PD Study Reports 5342-patient-pd-stud-rep
535-rep-effic-safety-stud
5.3.5 Reports of Efficacy and Safety Studies
Reports of Efficacy and Safety Studies –

5.3.5 indication-1
Indication Name
Study Reports of Controlled Clinical Studies
5.3.5.1 5351-stud-rep-contr
Pertinent to the Claimed Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies 5352-stud-rep-uncontr

Reports of Analyses of Data from More than
5.3.5.3 5353-rep-analys-data-more-one-stud
One Study
5.3.5.4 Other Study Reports 5354-other-stud-rep
Page 3-11
Section in
CTD
5.3.6 Reports of Postmarketing Experience 536-postmark-exp

Case Report Forms and Individual Patient
5.3.7 537-crf-ipl
Listings6
“Study Report 1” study-report-1

6
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
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
Appendix 4: File Organization for the eCTD
Each item in the file organization table that is listed in this appendix includes the information outlined below:
Sequential Each item in the table has a unique sequentially assigned reference number. These reference numbers can
number change with each version of this appendix.
Number CTD section number
Title CTD title
Element Element name in the Backbone
File/Directory 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
Comment Comments
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.
Where file names are presented in italics applicants would substitute these with file names in accordance with their own naming conventions.
Page 4-1
Table 4-1
Number
Title
1 Element
File index.xml
Comment This is the Backbone
Number
Title
2 Element
File index-md5.txt
Comment The MD5 of the Backbone
Page 4-2
Number 1
Title Administrative Information and Prescribing Information
3 Element m1-administrative-information-and-prescribing-information
Directory m1
Comment Only one of the regional directories is needed
Number
Title
Element
4
Directory 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
5
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
6
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
7
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
Page 4-3
Number 2
Title Common Technical Document Summaries
8 Element m2-common-technical-document-summaries
Directory m2
Comment
Number 2.2
Title Introduction
9 Element m2-2-introduction
Directory m2/22-intro
Comment
Number 2.2
Title Introduction
File m2/22-intro/introduction.pdf
Comment
Number 2.3
Title Quality Overall Summary
Element m2-3-quality-overall-summary
11
Directory
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
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
Page 4-4
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the
Quality Overall Summary
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'.
Number 2.3.P
Title Drug Product -Name
Elementm2-3-p-drug-product
File m2/23-qos/drug-product-name.pdf
14 Overall Summary
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., 'drug-
product-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
Comment
Overall Summary
Number 2.3.R
Title Regional Information
Element m2-3-r-regional-information
16
File m2/23-qos/regional-information.pdf
Comment
Overall Summary
17 Number 2.4
Page 4-5
Title Nonclinical Overview
Element m2-4-nonclinical-overview
Directory m2/24-nonclin-over
Comment
Number 2.4
Title Nonclinical Overview
Element m2-4-nonclinical-overview
18
File 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
Comment
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
Page 4-6
Comment
Number 2.6.3
Title Pharmacology Tabulated Summary
24 Element m2-6-3-pharmacology-tabulated-summary
File m2/26-nonclin-sum/pharmacol-tabulated-summary.pdf
Comment Should have further navigation via bookmarks
Number 2.6.4
Title Pharmacokinetics Written Summary
Element m2-6-4-pharmacokinetics-written-summary
25
File m2/26-nonclin-sum/pharmkin-written-summary.pdf
Comment
Number 2.6.5
Title Pharmacokinetics Tabulated Summary
26 Element m2-6-5-pharmacokinetics-tabulated-summary
File m2/26-nonclin-sum/pharmkin-tabulated-summary.pdf
Number 2.6.6
Title Toxicology Written Summary
Element m2-6-6-toxicology-written-summary
27
File m2/26-nonclin-sum/toxicology-written-summary.pdf
Comment
Number 2.6.7
Title Toxicology Tabulated Summary
28 Element m2-6-7-toxicology-tabulated-summary
File m2/26-nonclin-sum/toxicology-tabulated-summary.pdf
Number 2.7
Title Clinical Summary
29 Element m2-7-clinical-summary
Directory m2/27-clin-sum
Comment
30 Number 2.7.1
Page 4-7
Title Summary of Biopharmaceutic Studies and Associated Analytical Methods
Element m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analytical-methods
File m2/27-clin-sum/summary-biopharm.pdf
Comment
Number 2.7.2
Title Summary of Clinical Pharmacology Studies
Element m2-7-2-summary-of-clinical-pharmacology-studies
31
File m2/27-clin-sum/summary-clin-pharm.pdf
Comment
Number 2.7.3
Title Summary of Clinical Efficacy – Indication
Element m2-7-3-summary-of-clinical-efficacy
File m2/27-clin-sum/summary-clin-efficacy-indication.pdf
32 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
Comment second 'summary-clin-efficacy-migraine'.
Number 2.7.4
Title Summary of Clinical Safety
Element m2-7-4-summary-of-clinical-safety
33
File m2/27-clin-sum/summary-clin-safety.pdf
Comment
Number 2.7.5
Title Literature References
34 Element m2-7-5-literature-references
File m2/27-clin-sum/literature-references.pdf
Comment
35 Number 2.7.6
Title Synopses of Individual Studies
Element m2-7-6-synopses-of-individual-studies
File m2/27-clin-sum/synopses-indiv-studies.pdf
Page 4-8
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
Comment
considered sufficient to provide hyperlinks from the listing of the studies, located here, to the locations of the synopses in Module 5.
Page 4-9
Number 3
Title Quality
36 Element m3-quality
Directory m3
Comment Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for Module 3
Number 3.2
Title Body of Data
37 Element m3-2-body-of-data
Directory m3/32-body-data
Comment
Number 3.2.S
Title Drug Substance
38 Element m3-2-s-drug-substance
Directory m3/32-body-data/32s-drug-sub
Comment
39 Number 3.2.S
Title Drug Substance - Drug Substance Name - Manufacturer
Element m3-2-s-drug-substance
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1
Page 4-10
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.
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'.
Comment 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'.
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
Typically the applicant would include the specific manufacturer(s) (and/or site) in the folder name.
Number 3.2.S.1
Title General Information (name, manufacturer)
40 Element m3-2-s-1-general-information
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info
Comment
Number 3.2.S.1.1
Title Nomenclature (name, manufacturer)
41 Element m3-2-s-1-1-nomenclature
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/nomenclature.pdf
Comment
Number 3.2.S.1.2
Title Structure (name, manufacturer)
42 Element m3-2-s-1-2-structure
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/structure.pdf
Comment
43 Number 3.2.S.1.3
Page 4-11
Title General Properties (name, manufacturer)
Element m3-2-s-1-3-general-properties
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/general-properties.pdf
Comment
Number 3.2.S.2
Title Manufacture (name, manufacturer)
44 Element m3-2-s-2-manufacture
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf
Comment
Number 3.2.S.2.1
Title Manufacturer(s) (name, manufacturer)
45 Element m3-2-s-2-1-manufacturer
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manufacturer.pdf
Comment For this document there should be only information regarding one manufacturer
Number 3.2.S.2.2
Title Description of Manufacturing Process and Process Controls (name, manufacturer)
46 Element m3-2-s-2-2-description-of-manufacturing-process-and-process-controls
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manuf-process-and-controls.pdf
Comment
Number 3.2.S.2.3
Title Control of Materials (name, manufacturer)
47 Element m3-2-s-2-3-control-of-materials
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/control-of-materials.pdf
Comment
Number 3.2.S.2.4
Title Controls of Critical Steps and Intermediates (name, manufacturer)
48 Element m3-2-s-2-4-controls-of-critical-steps-and-intermediates
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/control-critical-steps.pdf
Comment
Number 3.2.S.2.5
Title Process Validation and/or Evaluation (name, manufacturer)
49 Element m3-2-s-2-5-process-validation-and-or-evaluation
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/process-validation.pdf
Comment
Page 4-12
Number 3.2.S.2.6
Title Manufacturing Process Development (name, manufacturer)
50 Element m3-2-s-2-6-manufacturing-process-development
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manuf-process-development.pdf
Comment
Number 3.2.S.3
Title Characterisation (name, manufacturer)
51 Element m3-2-s-3-characterisation
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac
Comment
Number 3.2.S.3.1
Title Elucidation of Structure and Other Characteristics (name, manufacturer)
52 Element m3-2-s-3-1-elucidation-of-structure-and-other-characteristics
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac/elucidation-of-structure.pdf
Comment
Number 3.2.S.3.2
Title Impurities (name, manufacturer)
53 Element m3-2-s-3-2-impurities
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac/impurities.pdf
Comment
Number 3.2.S.4
Title Control of Drug Substance (name, manufacturer)
54 Element m3-2-s-4-control-of-drug-substance
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub
Comment
Number 3.2.S.4.1
Title Specification (name, manufacturer)
55 Element m3-2-s-4-1-specification
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s41-spec
Comment
Number 3.2.S.4.1
Title Specification (name, manufacturer)
56 Element m3-2-s-4-1-specification
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s41-spec/specification.pdf
Comment
Page 4-13
Number 3.2.S.4.2
Title Analytical Procedures (name, manufacturer)
57 Element m3-2-s-4-2-analytical-procedures
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc
Comment The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
Number 3.2.S.4.2.1
Title Analytical Procedure-1
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc/analytical-procedure-1.pdf
Comment
Number 3.2.S.4.2.2
Comment
Number 3.2.S.4.2.3
Comment
Number 3.2.S.4.3
Title Validation of Analytical Procedures
61 Element m3-2-s-4-3-validation-of-analytical-procedures (name, manufacturer)
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc
Number 3.2.S.4.3.1
Title Validation of Analytical Procedure-1
62 Element m3-2-s-4-3-validation-of-analytical-procedures
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc/validation-analyt-procedure-1.pdf
Comment
63 Number 3.2.S.4.3.2
Element m3-2-s-4-3-validation-of-analytical-procedures
Page 4-14
Comment
Number 3.2.S.4.3.3
64 Element m3-2-s-4-3-validation-of-analytical-procedures
Comment
Number 3.2.S.4.4
Title Batch Analyses (name, manufacturer)
65 Element m3-2-s-4-4-batch-analyses
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s44-batch-analys
Comment
Number 3.2.S.4.4
Title Batch Analyses (name, manufacturer)
66 Element m3-2-s-4-4-batch-analyses
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s44-batch-analys/batch-analyses.pdf
Comment
Number 3.2.S.4.5
Title Justification of Specification (name, manufacturer)
67 Element m3-2-s-4-5-justification-of-specification
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s45-justif-spec
Comment
Number 3.2.S.4.5
Title Justification of Specification (name, manufacturer)
68 Element m3-2-s-4-5-justification-of-specification
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s45-justif-spec/justification-of-specification.pdf
Comment
Number 3.2.S.5
Title Reference Standards or Materials (name, manufacturer)
69 Element m3-2-s-5-reference-standards-or-materials
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand
Comment
70 Number 3.2.S.5
Title Reference Standards or Materials (name, manufacturer)
Element m3-2-s-5-reference-standards-or-materials
Page 4-15
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand/reference-standards.pdf
Comment Where a multiple file approach is taken for this section, the file names should indicate which reference standard is covered in the document.
Number 3.2.S.6
Title Container Closure System (name, manufacturer)
71 Element m3-2-s-6-container-closure-system
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys
Comment
Number 3.2.S.6
Title Container Closure System (name, manufacturer)
72 Element m3-2-s-6-container-closure-system
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys/container-closure-system.pdf
Comment
Number 3.2.S.7
Title Stability (name, manufacturer)
73 Element m3-2-s-7-stability
Directory m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab
Comment
Number 3.2.S.7.1
Title Stability Summary and Conclusions (name, manufacturer)
74 Element m3-2-s-7-1-stability-summary-and-conclusions
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/stability-summary.pdf
Comment
Number 3.2.S.7.2
Title Post-approval Stability Protocol and Stability Commitment (name, manufacturer)
75 Element m3-2-s-7-2-post-approval-stability-protocol-and-stability-commitment
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/postapproval-stability.pdf
Comment
Number 3.2.S.7.3
Title Stability Data (name, manufacturer)
76 Element m3-2-s-7-3-stability-data
File m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/stability-data.pdf
Comment
77 Number 3.2.P
Title Drug Product (name, dosage form)
Element m3-2-p-drug-product
Page 4-16
Directory m3/32-body-data/32p-drug-prod
Comment
Number 3.2.P
Title Drug Product (name, dosage form) – Name
Element m3-2-p-drug-product
Directory m3/32-body-data/32p-drug-prod/product-1
78 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., 'tablet-
5mg'. Where there is more than one drug product (e.g., powder for reconstitution and diluent) then the first drug product has a folder
Comment '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.
Number 3.2.P.1
Title Description and Composition of the Drug Product (name, dosage form)
79 Element m3-2-p-1-description-and-composition-of-the-drug-product
Directory m3/32-body-data/32p-drug-prod/product-1/32p1-desc-comp
Comment
Number 3.2.P.1
Title Description and Composition of the Drug Product (name, dosage form)
80 Element m3-2-p-1-description-and-composition-of-the-drug-product
File m3/32-body-data/32p-drug-prod/product-1/32p1-desc-comp/description-and-composition.pdf
Comment
Number 3.2.P.2
Title Pharmaceutical Development (name, dosage form)
Element m3-2-p-2-pharmaceutical-development
81
Directory 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
Comment
Development section.
Number 3.2.P.2
Title Pharmaceutical Development (name, dosage form)
Element m3-2-p-2-pharmaceutical-development
82 File m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev/pharmaceutical-development.pdf
Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical
Comment
Development section.
Page 4-17
Number 3.2.P.3
Title Manufacture (name, dosage form)
83 Element m3-2-p-3-manufacture
Directory m3/32-body-data/32p-drug-prod/product-1/32p3-manuf
Comment
Number 3.2.P.3.1
Title Manufacturer(s) (name, dosage form)
84 Element m3-2-p-3-1-manufacturers
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manufacturers.pdf
Comment
Number 3.2.P.3.2
Title Batch Formula (name, dosage form)
85 Element m3-2-p-3-2-batch-formula
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/batch-formula.pdf
Comment
Number 3.2.P.3.3
Title Description of Manufacturing Process and Process Controls (name, dosage form)
86 Element m3-2-p-3-3-description-of-manufacturing-process-and-process-controls
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manuf-process-and-controls.pdf
Comment
Number 3.2.P.3.4
Title Controls of Critical Steps and Intermediates (name, dosage form)
87 Element m3-2-p-3-4-controls-of-critical-steps-and-intermediates
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/control-critical-steps.pdf
Comment
Number 3.2.P.3.5
Title Process Validation and/or Evaluation (name, dosage form)
88 Element m3-2-p-3-5-process-validation-and-or-evaluation
File m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/process-validation.pdf
Comment The applicant has the option to submit one or multiple files, one for each validation or evaluation.
89 Number 3.2.P.4
Title Control of Excipients (name, dosage form)
Element m3-2-p-4-control-of-excipients
Directory m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip
Page 4-18
Comment
Number 3.2.P.4
Title Control of Excipients (name, dosage form) – Excipient
Element m3-2-p-4-control-of-excipients
90 Directory 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
Comment
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.
Number 3.2.P.4.1
Title Specifications (name, dosage form)
91 Element m3-2-p-4-1-specifications
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/specifications.pdf
Comment See comment under 3.2.P.4.
Number 3.2.P.4.2
Title Analytical Procedures (name, dosage form)
92 Element m3-2-p-4-2-analytical-procedures
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/analytical-procedures.pdf
Number 3.2.P.4.3
Title Validation of Analytical Procedures (name, dosage form)
93 Element m3-2-p-4-3-validation-of-analytical-procedures
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/validation-analyt-procedures.pdf
Number 3.2.P.4.4
Title Justification of Specifications (name, dosage form)
94 Element m3-2-p-4-4-justification-of-specifications
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/justification-of-specifications.pdf
Number 3.2.P.4.5
Title Excipients of Human or Animal Origin (name, dosage form)
95 Element m3-2-p-4-5-excipients-of-human-or-animal-origin
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipients-human-animal.pdf
Comment
96 Number 3.2.P.4.6
Page 4-19
Title Novel Excipients (name, dosage form)
Element m3-2-p-4-6-novel-excipients
File m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/novel-excipients.pdf
Comment
Number 3.2.P.5
Title Control of Drug Product (name, dosage form)
97 Element m3-2-p-5-control-of-drug-product
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod
Comment
Number 3.2.P.5.1
Title Specification(s) (name, dosage form)
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec
Comment
Number 3.2.P.5.1
Title Specification(s) (name, dosage form)
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec/specifications.pdf
Comment
Number 3.2.P.5.2
Title Analytical Procedures (name, dosage form)
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc
Number 3.2.P.5.2.1
Title Analytical Procedure – 1
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-1.pdf
Comment
Number 3.2.P.5.2.2
Comment
Page 4-20
Number 3.2.P.5.2.3
Comment
Number 3.2.P.5.3
Title Validation of Analytical Procedures (name, dosage form)
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc
Number 3.2.P.5.3.1
Title Validation of Analytical Procedures – 1
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc/validation-analytical-procedures-1.pdf
Comment
Number 3.2.P.5.3.2
Comment
Number 3.2.P.5.3.3
Comment
Number 3.2.P.5.4
Title Batch Analyses (name, dosage form)
108 Element m3-2-p-5-4-batch-analyses
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p54-batch-analys
Comment
109 Number 3.2.P.5.4
Title Batch Analyses (name, dosage form)
Element m3-2-p-5-4-batch-analyses
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p54-batch-analys/batch-analyses.pdf
Page 4-21
Comment
Number 3.2.P.5.5
Title Characterisation of Impurities (name, dosage form)
110 Element m3-2-p-5-5-characterisation-of-impurities
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p55-charac-imp
Comment
Number 3.2.P.5.5
Title Characterisation of Impurities (name, dosage form)
111 Element m3-2-p-5-5-characterisation-of-impurities
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p55-charac-imp/characterisation-impurities.pdf
Comment
Number 3.2.P.5.6
Directory m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec
Comment
Number 3.2.P.5.6
File m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec/justification-of-specifications.pdf
Comment
Number 3.2.P.6
Title Reference Standards or Materials (name, dosage form)
114 Element m3-2-p-6-reference-standards-or-materials
Directory m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand
Comment
Number 3.2.P.6
Title Reference Standards or Materials (name, dosage form)
115 Element m3-2-p-6-reference-standards-or-materials
File m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand/reference-standards.pdf
Comment When a multiple file approach is taken for this section, the file names should indicate which reference standard is covered in the document.
116 Number 3.2.P.7
Title Container Closure System (name, dosage form)
Element m3-2-p-7-container-closure-system
Directory m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys
Page 4-22
Comment
Number 3.2.P.7
Title Container Closure System (name, dosage form)
117 Element m3-2-p-7-container-closure-system
File m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys/container-closure-system.pdf
Comment
Number 3.2.P.8
Title Stability (name, dosage form)
118 Element m3-2-p-8-stability
Directory m3/32-body-data/32p-drug-prod/product-1/32p8-stab
Comment
Number 3.2.P.8.1
Title Stability Summary and Conclusion (name, dosage form)
119 Element m3-2-p-8-1-stability-summary-and-conclusion
File m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-summary.pdf
Comment
Number 3.2.P.8.2
Title Post-approval Stability Protocol and Stability Commitment (name, dosage form)
120 Element m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment
File m3/32-body-data/32p-drug-prod/product-1/32p8-stab/postapproval-stability.pdf
Comment
Number 3.2.P.8.3
Title Stability Data (name, dosage form)
121 Element m3-2-p-8-3-stability-data
File m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-data.pdf
Comment
Number 3.2.A
Title Appendices
122 Element m3-2-a-appendices
Directory m3/32-body-data/32a-app
Comment
123 Number 3.2.A.1
Title Facilities and Equipment (name, manufacturer)
Element m3-2-a-1-facilities-and-equipment
Directory m3/32-body-data/32a-app/32a1-fac-equip
Page 4-23
Several reports are likely to be included in this appendix. The organisation is left to the applicant to define. However, where there is more
Comment
than one manufacturer a folder should be created for each manufacturer and the identity of the manufacturer included in the directory name.
Number 3.2.A.1.1
Title Facilities and Equipment Report 1
124 Element m3-2-a-1-facilities-and-equipment
File m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-1.pdf
Comment
Number 3.2.A.1.2
Comment
Number 3.2.A.1.3
Comment
Number 3.2.A.2
Title Adventitious Agents Safety Evaluation (name, dosage form, manufacturer)
Element m3-2-a-2-adventitious-agents-safety-evaluation
127 Directory 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
Comment 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.
Number 3.2.A.2.1
Title Adventitious Agents Safety Evaluation Report 1
128 Element m3-2-a-2-adventitious-agents-safety-evaluation
File m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-1.pdf
Comment
Number 3.2.A.2.2
129 Element m3-2-a-2-adventitious-agents-safety-evaluation
Comment
130 Number 3.2.A.2.3
Page 4-24
Element m3-2-a-2-adventitious-agents-safety-evaluation
Comment
Number 3.2.A.3
Title Excipients – Name
Element m3-2-a-3-excipients
Directory m3/32-body-data/32a-app/32a3-excip-name-1
131 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'.
Comment
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.
Number 3.2.R
Title Regional Information
132 Element m3-2-r-regional-information
Directory m3/32-body-data/32r-reg-info
Comment Refer to the M4 Organisation Document: Granularity Annex for the approach to take with this section.
Number 3.3
133 Element m3-3-literature-references
Directory m3/33-lit-ref
Comment Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference).
Number 3.3.1
Title Reference 1
File m3/33-lit-ref/reference-1.pdf
Comment
Number 3.3.2
Title Reference 2
Comment
136 Number 3.3.3
Title Reference 3
Page 4-25
Element m3-3-literature-references
Comment
Page 4-26
Number 4
Title Nonclinical Study Reports
137 Element m4-nonclinical-study-reports
Directory m4
Comment
Number 4.2
Title Study Reports
138 Element m4-2-study-reports
Directory m4/42-stud-rep
Comment
Number 4.2.1
Title Pharmacology
139 Element m4-2-1-pharmacology
Directory m4/42-stud-rep/421-pharmacol
Comment
Number 4.2.1.1
Title Primary Pharmacodynamics
140 Element m4-2-1-1-primary-pharmacodynamics
Directory m4/42-stud-rep/421-pharmacol/4211-prim-pd
Comment
Number4.2.1.1.1
Title Study Report 1
Element
m4-2-1-1-primary-pharmacodynamics
File 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
141 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
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.
Page 4-27
Number 4.2.1.1.2
Comment
Number 4.2.1.1.3
Comment
Number 4.2.1.2
Title Secondary Pharmacodynamics
144 Element m4-2-1-2-secondary-pharmacodynamics
Directory m4/42-stud-rep/421-pharmacol/4212-sec-pd
Comment
Number 4.2.1.2.1
File m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-1.pdf
Comment
Number 4.2.1.2.2
Comment
Number 4.2.1.2.3
Comment
Number 4.2.1.3
Title Safety Pharmacology
148 Element m4-2-1-3-safety-pharmacology
Directory m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol
Comment
Page 4-28
Number 4.2.1.3.1
File m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-1.pdf
Comment
Number 4.2.1.3.2
Comment
Number 4.2.1.3.3
Comment
Number 4.2.1.4
Title Pharmacodynamic Drug Interactions
152 Element m4-2-1-4-pharmacodynamic-drug-interactions
Directory m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact
Comment
Number 4.2.1.4.1
File m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-1.pdf
Comment
Number 4.2.1.4.2
Comment
155 Number 4.2.1.4.3
Element m4-2-1-4-pharmacodynamic-drug-interactions
Page 4-29
Comment
Number 4.2.2
Title Pharmacokinetics
156 Element m4-2-2-pharmacokinetics
Directory m4/42-stud-rep/422-pk
Comment
Number 4.2.2.1
Title Analytical Methods and Validation Reports (if separate reports are available)
157 Element m4-2-2-1-analytical-methods-and-validation-reports
Directory m4/42-stud-rep/422-pk/4221-analyt-met-val
Comment
Number 4.2.2.1.1
File m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-1.pdf
Comment
Number 4.2.2.1.2
Comment
Number 4.2.2.1.3
Comment
Number 4.2.2.2
Title Absorption
161 Element m4-2-2-2-absorption
Directory m4/42-stud-rep/422-pk/4222-absorp
Comment
162 Number 4.2.2.2.1
Element m4-2-2-2-absorption
File m4/42-stud-rep/422-pk/4222-absorp/study-report-1.pdf
Page 4-30
Comment
Number 4.2.2.2.2
Comment
Number 4.2.2.2.3
Comment
Number 4.2.2.3
Title Distribution
165 Element m4-2-2-3-distribution
Directory m4/42-stud-rep/422-pk/4223-distrib
Comment
Number 4.2.2.3.1
File m4/42-stud-rep/422-pk/4223-distrib/study-report-1.pdf
Comment
Number 4.2.2.3.2
Comment
Number 4.2.2.3.3
Comment
169 Number 4.2.2.4
Title Metabolism
Element m4-2-2-4-metabolism
Directory m4/42-stud-rep/422-pk/4224-metab
Page 4-31
Comment
Number 4.2.2.4.1
170 Element m4-2-2-4-metabolism
File m4/42-stud-rep/422-pk/4224-metab/study-report-1.pdf
Comment
Number 4.2.2.4.2
Comment
Number 4.2.2.4.3
Comment
Number 4.2.2.5
Title Excretion
173 Element m4-2-2-5-excretion
Directory m4/42-stud-rep/422-pk/4225-excr
Comment
Number 4.2.2.5.1
File m4/42-stud-rep/422-pk/4225-excr/study-report-1.pdf
Comment
Number 4.2.2.5.2
Comment
176 Number 4.2.2.5.3
Element m4-2-2-5-excretion
Page 4-32
Comment
Number 4.2.2.6
Title Pharmacokinetic Drug Interactions (nonclinical)
177 Element m4-2-2-6-pharmacokinetic-drug-interactions
Directory m4/42-stud-rep/422-pk/4226-pk-drug-interact
Comment
Number 4.2.2.6.1
File m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-1.pdf
Comment
Number 4.2.2.6.2
Comment
Number 4.2.2.6.3
Comment
Number 4.2.2.7
Title Other Pharmacokinetic Studies
181 Element m4-2-2-7-other-pharmacokinetic-studies
Directory m4/42-stud-rep/422-pk/4227-other-pk-stud
Comment
Number 4.2.2.7.1
File m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-1.pdf
Comment
183 Number 4.2.2.7.2
Element m4-2-2-7-other-pharmacokinetic-studies
Page 4-33
Comment
Number 4.2.2.7.3
Comment
Number 4.2.3
Title Toxicology
185 Element m4-2-3-toxicology
Directory m4/42-stud-rep/423-tox
Comment
Number 4.2.3.1
Title Single-Dose Toxicity (in order by species, by route)
186 Element m4-2-3-1-single-dose-toxicity
Directory m4/42-stud-rep/423-tox/4231-single-dose-tox
Comment
Number 4.2.3.1.1
File m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-1.pdf
Comment
Number 4.2.3.1.2
Comment
Number 4.2.3.1.3
Comment
190 Number 4.2.3.2
Title Repeat-Dose Toxicity (in order by species, by route, by duration, including supportive toxicokinetics evaluations)
Page 4-34
Element m4-2-3-2-repeat-dose-toxicity
Directory m4/42-stud-rep/423-tox/4232-repeat-dose-tox
Comment
Number 4.2.3.2.1
191 Element m4-2-3-2-repeat-dose-toxicity
File m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-1.pdf
Comment
Number 4.2.3.2.2
Comment
Number 4.2.3.2.3
Comment
Number 4.2.3.3
Title Genotoxicity
194 Element m4-2-3-3-genotoxicity
Directory m4/42-stud-rep/423-tox/4233-genotox
Comment
Number 4.2.3.3.1
Title In vitro
195 Element m4-2-3-3-1-in-vitro
Directory m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro
Comment
Number 4.2.3.3.1.1
File m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-1.pdf
Comment
197 Number 4.2.3.3.1.2
Page 4-35
Element m4-2-3-3-1-in-vitro
Comment
Number 4.2.3.3.1.3
Comment
Number 4.2.3.3.2
Title In vivo (including supportive toxicokinetics evaluations)
199 Element m4-2-3-3-2-in-vivo
Directory m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo
Comment
Number 4.2.3.3.2.1
File m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-1.pdf
Comment
Number 4.2.3.3.2.2
Comment
Number 4.2.3.3.2.3
Comment
Number 4.2.3.4
Title Carcinogenicity (including supportive toxicokinetics evaluations)
203 Element m4-2-3-4-carcinogenicity
Directory m4/42-stud-rep/423-tox/4234-carcigen
Comment
204 Number 4.2.3.4.1
Page 4-36
Long-term studies (in order by species, including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
Title
pharmacokinetics)
Element m4-2-3-4-1-long-term-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud
Comment
Number 4.2.3.4.1.1
205 Element m4-2-3-4-1-long-term-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-1.pdf
Comment
Number 4.2.3.4.1.2
Comment
Number 4.2.3.4.1.3
Comment
Number 4.2.3.4.2
Short- or medium-term studies (including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
Title
pharmacokinetics)
208
Element m4-2-3-4-2-short-or-medium-term-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud
Comment
Number 4.2.3.4.2.1
209 Element m4-2-3-4-2-short-or-medium-term-studies
File m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-1.pdf
Comment
210 Number 4.2.3.4.2.2
Element m4-2-3-4-2-short-or-medium-term-studies
Page 4-37
Comment
Number 4.2.3.4.2.3
211 Element m4-2-3-4-2-short-or-medium-term-studies
Comment
Number 4.2.3.4.3
Title Other studies
212 Element m4-2-3-4-3-other-studies
Directory m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud
Comment
Number 4.2.3.4.3.1
File m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-1.pdf
Comment
Number 4.2.3.4.3.2
Comment
Number 4.2.3.4.3.3
Comment
Number 4.2.3.5
Reproductive and Developmental Toxicity (including range-finding studies and supportive toxicokinetics evaluations) (If modified study
Title
designs are used, the following subheadings should be modified accordingly)
216
Element m4-2-3-5-reproductive-and-developmental-toxicity
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox
Comment
217 Number 4.2.3.5.1
Title Fertility and early embryonic development
Element m4-2-3-5-1-fertility-and-early-embryonic-development
Page 4-38
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev
Comment
Number 4.2.3.5.1.1
218 Element m4-2-3-5-1-fertility-and-early-embryonic-development
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev/study-report-1.pdf
Comment
Number 4.2.3.5.1.2
Comment
Number 4.2.3.5.1.3
Comment
Number 4.2.3.5.2
Title Embryo-fetal development
221 Element m4-2-3-5-2-embryo-fetal-development
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev
Comment
Number 4.2.3.5.2.1
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-1.pdf
Comment
Number 4.2.3.5.2.2
Comment
224 Number 4.2.3.5.2.3
Page 4-39
Element m4-2-3-5-2-embryo-fetal-development
Comment
Number 4.2.3.5.3
Title Prenatal and postnatal development, including maternal function
225 Element m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev
Comment
Number 4.2.3.5.3.1
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-1.pdf
Comment
Number 4.2.3.5.3.2
Comment
Number 4.2.3.5.3.3
Comment
Number 4.2.3.5.4
Title Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
229 Element m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
Directory m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv
Comment
Number 4.2.3.5.4.1
File m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-1.pdf
Comment
231 Number 4.2.3.5.4.2
Page 4-40
Element m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
Comment
Number 4.2.3.5.4.3
Comment
Number 4.2.3.6
Title Local Tolerance
233 Element m4-2-3-6-local-tolerance
Directory m4/42-stud-rep/423-tox/4236-loc-tol
Comment
Number 4.2.3.6.1
File m4/42-stud-rep/423-tox/4236-loc-tol/study-report-1.pdf
Comment
Number 4.2.3.6.2
Comment
Number 4.2.3.6.3
Comment
Number 4.2.3.7
Title Other Toxicity Studies (if available)
237 Element m4-2-3-7-other-toxicity-studies
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud
Comment
238 Number 4.2.3.7.1
Title Antigenicity
Page 4-41
Element m4-2-3-7-1-antigenicity
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen
Comment
Number 4.2.3.7.1.1
239 Element m4-2-3-7-1-antigenicity
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-1.pdf
Comment
Number 4.2.3.7.1.2
Comment
Number 4.2.3.7.1.3
Comment
Number 4.2.3.7.2
Title Immunotoxicity
242 Element m4-2-3-7-2-immunotoxicity
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox
Comment
Number 4.2.3.7.2.1
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-1.pdf
Comment
Number 4.2.3.7.2.2
Comment
245 Number 4.2.3.7.2.3
Page 4-42
Element m4-2-3-7-2-immunotoxicity
Comment
Number 4.2.3.7.3
Title Mechanistic studies (if not included elsewhere)
246 Element m4-2-3-7-3-mechanistic-studies
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud
Comment
Number 4.2.3.7.3.1
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-1.pdf
Comment
Number 4.2.3.7.3.2
Comment
Number 4.2.3.7.3.3
Comment
Number 4.2.3.7.4
Title Dependence
250 Element m4-2-3-7-4-dependence
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep
Comment
Number 4.2.3.7.4.1
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-1.pdf
Comment
252 Number 4.2.3.7.4.2
Page 4-43
Element m4-2-3-7-4-dependence
Comment
Number 4.2.3.7.4.3
Comment
Number 4.2.3.7.5
Title Metabolites
254 Element m4-2-3-7-5-metabolites
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab
Comment
Number 4.2.3.7.5.1
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-1.pdf
Comment
Number 4.2.3.7.5.2
Comment
Number 4.2.3.7.5.3
Comment
Number 4.2.3.7.6
Title Impurities
258 Element m4-2-3-7-6-impurities
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp
Comment
Page 4-44
Number 4.2.3.7.6.1
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-1.pdf
Comment
Number 4.2.3.7.6.2
Comment
Number 4.2.3.7.6.3
Comment
Number 4.2.3.7.7
Title Other
262 Element m4-2-3-7-7-other
Directory m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other
Comment
Number 4.2.3.7.7.1
File m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-1.pdf
Comment
Number 4.2.3.7.7.2
Comment
265 Number 4.2.3.7.7.3
Element m4-2-3-7-7-other
Page 4-45
Comment
Number 4.3
Comment Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference).
Number 4.3.1
Title Reference 1
Comment
Number 4.3.2
Title Reference 2
Comment
Number 4.3.3
Title Reference 3
Comment
Page 4-46
Number 5
Title Clinical Study Reports
270 Element m5-clinical-study-reports
Directory m5
Comment
Number 5.2
Title Tabular Listing of all Clinical Studies
271 Element m5-2-tabular-listing-of-all-clinical-studies
Directory m5/52-tab-list
Comment
Number 5.2
Title Tabular Listing of all Clinical Studies
272 Element m5-2-tabular-listing-of-all-clinical-studies
File m5/52-tab-list/tabular-listing.pdf
Comment
Number 5.3
Title Clinical Study Reports
273 Element m5-3-clinical-study-reports
Directory m5/53-clin-stud-rep
Comment
Number 5.3.1
Title Reports of Biopharmaceutic Studies
274 Element m5-3-1-reports-of-biopharmaceutic-studies
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud
Comment
Number 5.3.1.1
Title Bioavailability (BA) Study Reports
275 Element m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep
Comment
276 Number 5.3.1.1.1
Element m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-1
Page 4-47
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
Comment
Number 5.3.1.1.3
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
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
Comment
282 Number 5.3.1.2.3
Page 4-48
Element m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Comment
Number 5.3.1.3
Title In vitro – In vivo Correlation Study Reports
283 Element m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep
Comment
Number 5.3.1.3.1
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep/study-report-1
Comment
Number 5.3.1.3.2
Comment
Number 5.3.1.3.3
Comment
Number 5.3.1.4
Title Reports of Bioanalytical and Analytical Methods for Human Studies
287 Element m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met
Comment
Number 5.3.1.4.1
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met/study-report-1
Comment
289 Number 5.3.1.4.2
Page 4-49
Element m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
Comment
Number 5.3.1.4.3
Comment
Number 5.3.2
Title Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
291 Element m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat
Comment
Number 5.3.2.1
Title Plasma Protein Binding Study Reports
292 Element m5-3-2-1-plasma-protein-binding-study-reports
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep
Comment
Number 5.3.2.1.1
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep/study-report-1
Comment
Number 5.3.2.1.2
Comment
Number 5.3.2.1.3
Comment
296 Number 5.3.2.2
Title Reports of Hepatic Metabolism and Drug Interaction Studies
Page 4-50
Element m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud
Comment
Number 5.3.2.2.1
297 Element m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud/study-report-1
Comment
Number 5.3.2.2.2
Comment
Number 5.3.2.2.3
Comment
Number 5.3.2.3
Title Reports of Studies Using Other Human Biomaterials
300 Element m5-3-2-3-reports-of-studies-using-other-human-biomaterials
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat
Comment
Number 5.3.2.3.1
Directory m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-1
Comment
Number 5.3.2.3.2
Comment
303 Number 5.3.2.3.3
Page 4-51
Element m5-3-2-3-reports-of-studies-using-other-human-biomaterials
Comment
Number 5.3.3
Title Reports of Human Pharmacokinetic (PK) Studies
304 Element m5-3-3-reports-of-human-pharmacokinetics-pk-studies
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud
Comment
Number 5.3.3.1
Title Healthy Subject PK and Initial Tolerability Study Reports
305 Element m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep
Comment
Number 5.3.3.1.1
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep/study-report-1
Comment
Number 5.3.3.1.2
Comment
Number 5.3.3.1.3
Comment
Number 5.3.3.2
Title Patient PK and Initial Tolerability Study Reports
309 Element m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep
Comment
310 Number 5.3.3.2.1
Page 4-52
Element m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep/study-report-1
Comment
Number 5.3.3.2.2
Comment
Number 5.3.3.2.3
Comment
Number 5.3.3.3
Title Intrinsic Factor PK Study Reports
313 Element m5-3-3-3-intrinsic-factor-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep
Comment
Number 5.3.3.3.1
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-1
Comment
Number 5.3.3.3.2
Comment
Number 5.3.3.3.3
Comment
317 Number 5.3.3.4
Page 4-53
Title Extrinsic Factor PK Study Reports
Element m5-3-3-4-extrinsic-factor-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep
Comment
Number 5.3.3.4.1
318 Element m5-3-3-4-extrinsic-factor-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep/study-report-1
Comment
Number 5.3.3.4.2
Comment
Number 5.3.3.4.3
Comment
Number 5.3.3.5
Title Population PK Study Reports
321 Element m5-3-3-5-population-pk-study-reports
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep
Comment
Number 5.3.3.5.1
Directory m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep/study-report-1
Comment
Number 5.3.3.5.2
Comment
Page 4-54
Number 5.3.3.5.3
Comment
Number 5.3.4
Title Reports of Human Pharmacodynamic (PD) Studies
325 Element m5-3-4-reports-of-human-pharmacodynamics-pd-studies
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud
Comment
Number 5.3.4.1
Title Healthy Subject PD and PK/PD Study Reports
326 Element m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep
Comment
Number 5.3.4.1.1
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep/study-report-1
Comment
Number 5.3.4.1.2
Comment
Number 5.3.4.1.3
Comment
330 Number 5.3.4.2
Title Patient PD and PK/PD Study Reports
Element m5-3-4-2-patient-pd-and-pk-pd-study-reports
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep
Page 4-55
Comment
Number 5.3.4.2.1
331 Element m5-3-4-2-patient-pd-and-pk-pd-study-reports
Directory m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep/study-report-1
Comment
Number 5.3.4.2.2
Comment
Number 5.3.4.2.3
Comment
Number 5.3.5
Title Reports of Efficacy and Safety Studies
334 Element m5-3-5-reports-of-efficacy-and-safety-studies
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud
Comment
Number 5.3.5
Title Reports of Efficacy and Safety Studies - Indication Name
Element m5-3-5-reports-of-efficacy-and-safety-studies
335
Directory
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
Element m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
Page 4-56
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-1
Comment
Number 5.3.5.1.2
Comment
Number 5.3.5.1.3
Comment
Number 5.3.5.2
Title Study Reports of Uncontrolled Clinical Studies
340 Element m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr
Comment
Number 5.3.5.2.1
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr/study-report-1
Comment
Number 5.3.5.2.2
Comment
Number 5.3.5.2.3
Comment
344 Number 5.3.5.3
Title Reports of Analyses of Data from More than One Study
Element m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
Page 4-57
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud
Comment
Number 5.3.5.3.1
345 Element m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud/study-report-1
Comment
Number 5.3.5.3.2
Comment
Number 5.3.5.3.3
Comment
Number 5.3.5.4
Title Other Study Reports
348 Element m5-3-5-4-other-study-reports
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep
Comment
Number 5.3.5.4.1
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep/study-report-1
Comment
Number 5.3.5.4.2
Comment
351 Number 5.3.5.4.3
Page 4-58
Element m5-3-5-4-other-study-reports
Comment
Number 5.3.6
Title Reports of Postmarketing Experience
352 Element m5-3-6-reports-of-postmarketing-experience
Directory m5/53-clin-stud-rep/536-postmark-exp
Comment
Number 5.3.7
Title Case Report Forms and Individual Patient Listings
353 Element m5-3-7-case-report-forms-and-individual-patient-listings
Directory m5/53-clin-stud-rep/537-crf-ipl
Comment
Number 5.3.7.1
Title Study 1
Directory m5/53-clin-stud-rep/537-crf-ipl/study-1
Comment
Number5.3.7.1.1
Title Document/Dataset 1
Element
m5-3-7-case-report-forms-and-individual-patient-listings
355
File 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
File m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-2.pdft
Comment
Number 5.3.7.1.3
Comment
Page 4-59
Number 5.3.7.2
Title Study 2
Comment define element
Number 5.3.7.2.1
Comment
Number 5.3.7.2.2
Comment
Number 5.3.7.2.3
Comment
Number 5.3.7.3
Title Study 3
Comment define element
Number 5.3.7.3.1
Comment
364 Number 5.3.7.3.2
Element m5-3-7-case-report-forms-and-individual-patient-listings
Page 4-60
Comment
Number 5.3.7.3.3
Comment
Number 5.4
Comment Copies of literature references should ordinarily be submitted as individual files (i.e,. one for each reference).
Number 5.4.1
Title Reference 1
Comment
Number 5.4.2
Title Reference 2
Comment
Number 5.4.3
Title Reference 3
Comment
Page 4-61
Number
Title
370 Element
Directory util
Comment utilities
Number
Title
371 Element
Directory util/dtd
Comment DTDs – it is not necessary to include regional DTDs other than the one for the region to which the application is being made
Number
Title
372 Element
File util/dtd/ich-ectd-3-2.dtd
Comment DTD for the instance – the version used to create the eCTD submission must be included
Number
Title
373 Element
File util/dtd/eu-regional-1-0.dtd
Comment DTD for the EU specific documentation
Number
Title
374 Element
File util/dtd/jp-regional-1-0.dtd
Comment DTD for the Japan specific documentation
Number
Title
375 Element
File util/dtd/us-regional-1-0.dtd
Comment DTD for the US specific documentation
376 Number
Title
Element
Page 4-62
File util/dtd/xx-regional-1-0.dtd
Comment DTD for the xx specific documentation, where xx is a two character country code from ISO-3166-1
Number
Title
377 Element
Directory util/style
Comment Directory for style sheets – default (ICH) and applicant specific stylesheets
Number
Title
378 Element
File util/style/ectd-1-0.xsl
Comment The specific version of the eCTD stylesheet used by the applicant as a reference during the creation of the submission should be included.
Page 4-63
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 Internet Address Electronic Mail Contact
European Union http://www.emea.eu.int esubmission@emea.eu.int
Food And Drug Administration, http://www.fda.gov/cber Esubprep@cber.fda.gov
USA http://www.fda.gov/cder esub@cder.fda.gov
Ministry of Health, Labour and http://www.mhlw.go.jp e-submission@nihs.go.jp

Welfare, Japan http://www.nihs.go.jp
Health Canada http://www.hc-sc.gc.ca/hpb- mike_ward@hc-sc.gc.ca
dgps/therapeut
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 Reference location
EMEA, European Union http://www.eudra.org/
or national agencies http://heads.medagencies.org
Ministry of Health, Labour and Welfare, Japan http://www.mhlw.go.jp
http://www.nihs.go.jp
Food and Drug Administration, United States of http://www.fda.gov/
America
Health Canada, Health Protection Branch, Canada http://www.hc-sc.gc.ca/hpb-dgps/therapeut
Page 5-1
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 read-
only 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 Sequence number Type of submission
ctd-123456 0000 Original Submission
ctd-123456 0001 First amendment, supplement or
variation
ctd-123456 0002 Second amendment, supplement
or variation
…
ctd-123456 nnnn Nth amendment, supplement or
variation
Page 6-1
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, index-
md5.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 Files
ctd-123456/0000 index.xml
index-md5.txt
ctd-123456/0000/m1/us us-regional.xml
ctd-123456/0000/util ich-ectd-3-2.dtd
us-regional-1-0.dtd
index-md5.txt
ctd-123456/0001/util/dtd ich-ectd-3-2.dtd
us-regional-1-0.dtd
index-md5.txt
ctd-123456/0002/util/dtd 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 file’s 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
What the reviewer might see

Operation when using the Agency review
attribute software
value Meaning This file Previous file
New The file has no relationship with files submitted Current
previously.
Append This means there is an existing file to which this new Current Current -
file should be associated. (e.g., providing missing or Appended
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).
Replace This means there is an existing file that this new file Current Replaced
replaces.
Delete There is no new file submitted in this case. Instead, the No longer
leaf has the operation of “delete” and the “modified- relevant to the
file” attribute identifies the file in a previous submission review
that is to be considered 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:
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.

Table 6-4
Submission File name Operation File Being Sample logical display
sequence # Modified in a review tool
0000 0000\…\structure.pdf New 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
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
- 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.
Table 6-6
Submission File name Operation Modified file Sample logical
sequence # display in a review
tool
0001 0001\…\structure.pdf Append 0000\...\structure.pdf 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
- 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.
Table 6-7
Submission File name Operation File Being Sample logical display in
sequence # Modified a review tool
0000 0000\...\structure.pdf New structure.pdf (current)
0001 Delete 0000\...\structure.pdf 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. 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.
2. You should create a child <leaf> element underneath the <m2-4-nonclinical-overview> tag.
3. 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.
4. You should provide a descriptive title for the file that contains the nonclinical overview in the <title>
element of the <leaf>.
5. 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 Description/Instructions Example
Any table of A table of contents tag represents a
contents tag grouping of one or more files related
such as <m2- to a specific section of the Common
4- Technical Document.
nonclinical- One or more child <leaf> elements
overview> can be declared for a parent table of
contents tag.
It is possible to extend a table of
contents tag by providing a <node-
extension> 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
<leaf> 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
modified- The purpose of the modified-file modified-
file 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.
Page 6-8
operation Indicates the operation to be New
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 submitter’s internal version V23.5
number or version identification for
the report.
xlink:actuate Not Currently Used
xlink:href Provide the pointer to the actual file. 0000/m2/27-clin-sum/literature-
Use the relative path to the file and references.pdf
the file name.
xlink:role Not Currently Used
xlink:show Not Currently Used.
xlink:type Fixed value of “simple”. simple
keywords Not Currently Used
<title> This element is associated with a study report 1234
“leaf” and provides a description of
the file being submitted.
ID Unique identifier for this location in a1234567
the XML instance. Leaf ID must start
with a character.
Instructions for a Simple New Submission7

The following XML fragment demonstrates the submission of a clinical overview of efficacy as a single
PDF document.

<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<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>
</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 ctd-
123456\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 ctd-
123456\0001 directory and below.

<leaf ID=”a123457” operation = "replace"
xlink:type = "simple" checksum-type=“md5” checksum =
"e854d3002c02a61fe5cbe926fd973401"
application-version = "Acrobat 5"
modified-file = "../0000/index.xml#a123456">
<title>Clinical Overview</title>
</leaf>
</ectd:ectd>
Instructions for Multiple Indications

Multiple therapeutic indications use an additional attribute associated with the <m2-7-3-summary-of-
clinical-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
<m2-7-3-summary-of-clinical-efficacy> Indication Name of the indication pain
<m5-3-5-reports-of-efficacy-and-safety-studies> Indication Name of the indication. 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:

<m2-7-clinical-summary>
<m2-7-3-summary-of-clinical-efficacy indication = "pain">
<leaf ID=”s123456”operation = "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 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-clinical-summary>
<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" checksum-
type=“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 indication = "nausea">
<leaf ID=”a123459” operation = "new" xlink:type = "simple" checksum-
type=“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-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
<m3-2-s-drug-substance> Substance Name of one of the drug substances Acetaminophen
Manufacturer Name of the manufacturer of the drug substance my supplier
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 substance = "acetaminophen" manufacturer = "bulk company 2">
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 substance = "codeine" manufacturer = "drug company 2">
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-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
<m3-2-p-drug-product> product-name Name of one of the drug products Wonder drug
dosageform Dosage form and strength of the drug product Tablet-5 mg
manufacturer Manufacturer of the drug product Company A
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-and-
composition.pdf">
<title>wonder drug capsule product information</title>
</leaf>
<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-and-
composition.pdf">
<title>wonder drug tablet product data</title>
</leaf>
</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. 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.
2. Do not extend the element more than one level. For example, you should not extend <node-
extension> <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-r-
regional-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-regional-
information> element without the use of a “node extension”.
<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>
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 <node-
extension>. 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.
checksum =
"e854d3002c02a61fe5cbe926fd973401" ID=“ID050520”
application-version = "Acrobat 5">
Page 6-13
<title>Paper Submission </title>
</leaf>
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 reviewer’s computer. Font substitution can affect a document’s 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/in-
notes/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 Agency’s 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.
8
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' ?>





<!ELEMENT ectd:ectd (m1-administrative-information-and-prescribing-information? , m2-common-
technical-document-summaries? , m3-quality? , m4-nonclinical-study-reports? , m5-clinical-study-
reports?)>
<!ATTLIST ectd:ectd xmlns:ectd CDATA #FIXED 'http://www.ich.org/ectd'

xmlns:xlink CDATA #FIXED 'http://www.w3c.org/1999/xlink'
dtd-version CDATA #FIXED '3.2' >



<!ELEMENT leaf (title , link-text?)>
<!ATTLIST leaf ID ID #REQUIRED

operation (new | append | replace | delete ) #REQUIRED
checksum CDATA #REQUIRED
checksum-type CDATA #REQUIRED
xlink:type CDATA #FIXED 'simple'
xlink:show (new | replace | embed | other | none ) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none ) #IMPLIED
xml:lang CDATA #IMPLIED >
<!ATTLIST title ID ID #IMPLIED >

<!ATTLIST link-text ID ID #IMPLIED >

<!ATTLIST xref ID ID #REQUIRED

xlink:type CDATA #FIXED 'simple'
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
Page 8-2
xml:lang CDATA #IMPLIED >



<!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-quality-
overall-summary? , m2-4-nonclinical-overview? , m2-5-clinical-overview? , m2-6-nonclinical-written-and-
tabulated-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* , m2-3-
p-drug-product* , m2-3-a-appendices? , m2-3-r-regional-information?)>
<!ATTLIST m2-3-quality-overall-summary %att; >

<!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? , m2-6-2-
pharmacology-written-summary? , m2-6-3-pharmacology-tabulated-summary? , m2-6-4-pharmacokinetics-
written-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-and-
associated-analytical-methods? , m2-7-2-summary-of-clinical-pharmacology-studies? , m2-7-3-summary-
of-clinical-efficacy* , m2-7-4-summary-of-clinical-safety? , m2-7-5-literature-references? , m2-7-6-
synopses-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-a-
appendices? , 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-or-
materials? , m3-2-s-6-container-closure-system? , m3-2-s-7-stability?)>
<!ATTLIST m3-2-s-drug-substance %att;

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-of-
manufacturing-process-and-process-controls? , m3-2-s-2-3-control-of-materials? , m3-2-s-2-4-controls-of-
critical-steps-and-intermediates? , m3-2-s-2-5-process-validation-and-or-evaluation? , m3-2-s-2-6-
manufacturing-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 | node-
extension)*)>
<!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-other-
characteristics? , 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-4-2-
analytical-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-7-2-
post-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 | node-
extension)*)>
<!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* , m3-
2-p-5-control-of-drug-product? , m3-2-p-6-reference-standards-or-materials? , m3-2-p-7-container-closure-
system? , m3-2-p-8-stability?)>
<!ATTLIST m3-2-p-drug-product %att;

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-critical-
steps-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 | node-
extension)*)>
<!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-analytical-
procedures? , 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-5-2-
analytical-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; >

<!ATTLIST m3-2-p-5-1-specifications %att; >

<!ATTLIST m3-2-p-5-2-analytical-procedures %att; >

<!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
<!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-8-2-
post-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 | node-
extension)*)>
<!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-adventitious-
agents-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
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;

product-name CDATA #IMPLIED >
<!ELEMENT m3-2-a-3-excipients ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-3-excipients %att; >

<!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? , m4-2-3-
toxicology?)>
Page 8-8
<!ATTLIST m4-2-study-reports %att; >
<!ELEMENT m4-2-1-pharmacology (leaf* , m4-2-1-1-primary-pharmacodynamics? , m4-2-1-2-
secondary-pharmacodynamics? , m4-2-1-3-safety-pharmacology? , m4-2-1-4-pharmacodynamic-drug-
interactions?)>
<!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? , m4-2-2-6-
pharmacokinetic-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-or-
medium-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-early-
embryonic-development? , m4-2-3-5-2-embryo-fetal-development? , m4-2-3-5-3-prenatal-and-postnatal-
development-including-maternal-function? , m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-
are-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 | node-
extension)*)>
<!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-further-
evaluated ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-
evaluated %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? , m4-2-3-7-2-
immunotoxicity? , 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; >
Page 8-10
<!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 m5-clinical-study-reports (leaf* , m5-2-tabular-listing-of-all-clinical-studies? , m5-3-clinical-
study-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? , m5-3-2-
reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials? , m5-3-3-reports-of-human-
pharmacokinetics-pk-studies? , m5-3-4-reports-of-human-pharmacodynamics-pd-studies? , m5-3-5-reports-
of-efficacy-and-safety-studies* , m5-3-6-reports-of-postmarketing-experience? , m5-3-7-case-report-forms-
and-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-study-
reports? , 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 | node-
extension)*)>
<!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-drug-
interaction-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)*)>
Page 8-11
<!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 | node-
extension)*)>
<!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-pk-
and-initial-tolerability-study-reports? , m5-3-3-2-patient-pk-and-initial-tolerability-study-reports? , m5-3-3-
3-intrinsic-factor-pk-study-reports? , m5-3-3-4-extrinsic-factor-pk-study-reports? , m5-3-3-5-population-
pk-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-subject-
pd-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-controlled-
clinical-studies-pertinent-to-the-claimed-indication? , m5-3-5-2-study-reports-of-uncontrolled-clinical-
studies? , m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study? , m5-3-5-4-other-study-
reports?)>
<!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
<!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)*)>
Page 8-12
<!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-extension)*)>
<!ATTLIST m5-3-5-4-other-study-reports %att; >

<!ELEMENT m5-3-6-reports-of-postmarketing-experience ((leaf | node-extension)*)>
<!ATTLIST m5-3-6-reports-of-postmarketing-experience %att; >

<!ELEMENT m5-3-7-case-report-forms-and-individual-patient-listings ((leaf | node-extension)*)>
<!ATTLIST m5-3-7-case-report-forms-and-individual-patient-listings %att; >

Page 8-13
Appendix 9: Glossary
This glossary provides the definition of terms associated with the eCTD.
Architecture
A general term for the design and construction of computer systems, including technical infrastructure,
information (data), and applications.
ASCII
American Standard Code for Information Interchange. A specification for representing text as computer-
readable information.
Bookmark
A bookmark is a type of link with representative that links to a different view or page in a document.
Browser
A program that allows the user to read hypertext, to view contents of Web pages, and to navigate from one
page to another (e.g., Netscape Navigator, Mosaic, Microsoft Internet Explorer.)
Common Technical Document (CTD)

A harmonized format for a regulatory dossier that is considered acceptable in Japan, Europe, the United
States and Canada.
Decryption
To reverse encryption.
Directory (see also Folder)

The operating system method of organizing and providing access to individual files. Also called a folder.
DTD
Document Type Definition. A hierarchical organization or representation of the information contents of a
document utilized by SGML or XML.
eCTD
The electronic format of the ICH Common Technical Document
Encryption
The process of reversibly confusing text or data using a secret formula.
ESTRI
Electronic Standards for the Transfer of Regulatory Information.
EWG
Expert Working Group.
Folder (see also Directory)

The operating system method of organizing and providing access to individual files. Also called a
directory.
HTML
Hypertext Markup Language. Commonly used to format Web pages.
Hypertext
Page 9-1
A system that enables links to be established between specific words or figures in a document to other text,
tables or image allowing quick access to the linked items (such as on the World Wide Web).
ICH
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use.
Infrastructure
The basic support services for computing; the hardware, operating system, and network on which
applications and data are stored and on which the database management systems run.
Internet
The world-wide network of computers for accessing, sending, sharing, and transferring information
between sites at different locations. It is uncontrolled and unadministered, and when you connect to the
Internet, you actually become a part of it.
ISO
International Standards Organization, founded in 1946, it is the principal international standards-setting
organization.
Leaf
The eCTD DTD XML element that describes the content to be provided. The leaf consists of a file and the
meta-data associated with that file. Such files are placed in a directory structure that is similar to branches
of a tree.
Logical Document
One or more CTD table of contents sections that together contain the minimum amount of information to
be exchanged. Ideally, this is a single physical file.
M2
Multidisciplinary Group 2 (ESTRI) of ICH.
Network
A communication system that connects different computers and enables them to share peripherals such as
printers, disk drives and databases. Users (clients) can access applications and databases connected by the
network.
Node Extension
The extension of the definition of an element beneath a defined table of contents tag.
PDF
Portable Document Format, a proprietary (Adobe Systems) de facto standard for the electronic transfer of
documents.
SGML
Standardized Generalized Markup Language. An ISO standard for describing structured information in a
platform independent manner.
Software or Software Application

Computer program or application. There are two principal types: system software (e.g., computer operating
system or a utility program) (sometimes called a driver) for printing) and application software (e.g., an
accounts package or CAD program.)
Page 9-2
Standard
A technical specification that addresses a business requirement, has been implemented in viable
commercial products, and, to the extent practical, complies with recognized standards organizations such as
ISO.
Web page
Any page on the World Wide Web. The page usually offers the reader access to other topics of interest.
World Wide Web (WWW)

Segment of the Internet offering point-and-click (hypertext) access to information (as text, image or sound)
on an enormous number of topics from around the world.
XML
Extensible Markup Language. An ISO standard for describing structured information in a platform-
independent manner.
Page 9-3
SECTION 14
eSUBs and eCTD:

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.
eSUBS and eCTDs:
Practical Advice and
Pitfalls to Avoid
Ginny Ventura
Regulatory Information Specialist
CDER, U.S. FDA
June 21, 2006
Overview
• CDER’s eCTD processing
• How our tools look and work
• Frequently encountered issues
• Examples
• How to ensure success
Fewer Technical Issues
• eCTD submissions continue to increase

steadily
• Number of technical errors/issues has
decreased
• You’re doing a great job!
How CDER EDR Staff Checks Your
eCTD Submission
• Media is loaded to server, validate

program is run
• Directory compare tool is run
• If review of your submission cannot
proceed, you are contacted
• Otherwise, reviewers are notified that
submission is available for review
• Reviewer performs the detailed audit

General Sample – Module 1 -Risk Management
Life Cycle Sample – Stability Data Replaced
Navigation Pane
Life Cycle Sample – Stability Data Replaced
Detail Panel
The Top Technical Issues
• Listed from least to most important
• Most all errors stem from one or more of
these items
Use of Elements
• Not necessary to use every element in the

eCTD Specification
• Use only the elements you need
• Placeholder documents are not necessary,
and can divert reviewers’ time and
attention
Leaf Titles
• Should be informative and succinct

• Should not include the eCTD numbering
• Should immediately reveal to the reviewer
what’s inside
Clinical Reports – Long and
Short Leaf Titles in Navigation
Always Reference All Files 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 may not be located by
reviewers
Include Module 1 in All eCTD
Submissions
– Every eCTD Submission Requires Module 1
– Module 1 Identifies important information

• Company Name
• Drug Name
• Submission Type
• Submission Date
• Application Number
• Sequence Number
Make Sure All Application
Numbers are 6 Digits
– Application-number values must be 6 digits
• No spaces
• Six Numbers – pad left “0” if 5 digits are given
– Application number is key - ties all
submissions together as an application
Make Sure All Sequence
Numbers are 4 Digits
– Sequence-number values must be 4 digits
• No spaces
– Sequence number is key and relates all
submission components together
– Sequence numbers need not be
received/submitted in “sequence”
Do Not Use Node Extensions
– 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
Verify That All MD5 Checksums
are Correct
– MD5 Checksum values should be
• 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 each sequence number
directory
All Documents Should 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
All XML must use 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
Be Sure All PDF Hyperlinks &

Bookmarks are Correct
– Validate all Hyperlinks and Bookmarks
– Broken hyperlinks and bookmarks diminish
reviewer confidence in the submission
– Test before you submit

Book Mark Example to Avoid
Include TOCs In All PDF
Documents
For each Document
– If a paper document needs a TOC, a PDF
document needs a hyperlinked TOC
– TOCs should begin a PDF document if
possible
– Include both bookmarks and hyperlinks
– Cross Document Links work in an eCTD
To Summarize
• Correct use of elements and leaf titles

• Always Reference All Files in the XML Backbone(s)
• Include Module 1 in All eCTD Submissions
• Make Sure All Application Numbers are 6 Digits
• Make Sure All Sequence Numbers are 4 Digits
• Do Not Use Node Extensions
• Verify That All MD5 Checksums are Correct
All Documents Should Conform to eCTD Granularity
• All XML must use standard components
• Be Sure All PDF Hyperlinks & Bookmarks are Correct
• Include TOCs In All PDF Documents

Ensuring Success
• Submit a Sample eCTD prior to your real
eCTD (contact info next slide)
• Follow the specifications and guidances
and/or use an experienced consultant
• Follow the advice outlined in this

presentation to avoid common problems
References
• CDER Contact for information on eCTD and

CTD submissions: eSub@fda.hhs.gov
Review website
www.fda.gov/cder/regulatory/ersr/default.htm

www.ich.org
• Regulatory Review Support Staff, Office of
Business Process Support, CDER (headed by
Gary Gensinger)
SECTION 15
Evaluation and Research ISS/ISSE:

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.
ISS/ISE:
Where Do They Fit
in the CTD/eCTD?
Justina A. Molzon, M.S. Pharm., J.D.

Associate Director for International Programs
U.S. Food and Drug Administration
Session 317
Medical/Scientific Writing Track
Learning objectives
At the conclusion of this session, participants should be able to:
1. Differentiate between ICH guidelines and

FDA requirements for the CTD/eCTD.
2. Identify the goals of the CTD/eCTD for
both industry and regulators.
3. Identify strategies to include the ISS/ISE
in the CTD and eCTD submission
formats.
2
ICH
INTERNATIONAL CONFERENCE ON
HARMONIS/ZATION
of
Technical Requirements
for the Registration of
Pharmaceuticals for Human Use
http://www.ich.org
Hosted by ICH Secretariat
IFPMA-Geneva, Switzerland
A Unique Approach
• ICH was created in 1990
• Agreement between the EU, Japan and the
USA to harmonize different regional
requirements for registration of
pharmaceutical drug products
• Unique because joint effort by regulators and
associated pharmaceutical industry trade
associations
ICH Objectives
• Identification and elimination of the need to

duplicate studies to meet different regulatory
requirements
• More efficient use of resources in the R&D
process, as a consequence
• Quicker access for patients to safe and effective
new medicines
Harmonized Guidelines
• Efficacy - 13 topic headings/18 guidelines
• Safety - 8 topic headings/16 guidelines
• Quality - 9 topic headings/25 guidelines
• Multidisciplinary (Regulatory Communications)
– Medical Dictionary - MedDRA
– Electronic Standards - ESTRI, E2B
• In 1996 ICH industry representatives proposed
assembling the information generated by these
harmonized guidances in the same order
• Goal was to decrease the amount of time and
staff needed to assemble and disassemble
documents for submission to ICH regions
Common Technical Document
1.0 Regional Administrative Information

1.1 ToC of Module 1 or overall ToC,
including Module 1
Module 1
1.0 2.1 ToC of the CTD (Mod 2,3,4,5)
2.1 2.2 Introduction

Module 2 2.3 Quality Overall Summary
2.2
2.4 Nonclinical Overview
2.4 2.5
2.5 Clinical Overview
2.3
2.6 2.7 2.6 Nonclinical Summary
Module 3 Module 4 Module 5 2.7 Clinical Summary

Quality Nonclinical Clinical
3.0 Study Reports Study Reports Source: ICH Implementation Coordination Group
4.0 5.0
Format vs. Content
• The CTD provides a common format for the
submission of information to regulatory
authorities in the three ICH regions.
• However, the CTD does not address the
content of submissions.
– Regional requirements (ISS/ISE)
– Applicants preferences
• Dossier using the CTD format (Modules 2 to
5) will not be identical for all ICH regions
July 1, 2003
CTD mandatory in the EU and Japan
• “Highly Recommended” by FDA

• ICH documents have always been considered GUIDANCE
by FDA
• Good Guidance Practice (GGPs)
– Final Rule September 19, 2000
– GGPs require that the CTD not be mandatory
• Due to Regulation--Not an indication of lack of commitment
to ICH or the CTD
• Submissions indicate that sponsors are following this
recommendation
CTD Major Issue
Integrated Summary of Safety
Integrated Summary of Efficacy
• The name ”summary” has caused great
confusion
• Not a summary but an integrated analysis
• Critical components of the safety and
efficacy review and expected to be part of
FDA submission.
CTD- Efficacy Question # 10
• 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)?
ANSWER
• The ISS/ISE are critical components of the
safety and effectiveness submission and
expected to be submitted in the application in
accordance with the regulation. FDA’s
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.
• 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.
Updated CTD-E Q&A #10
• Based on experience with CTD/eCTD
submissions
• Language submitted to ICH Secretariat for
discussion with ICH Steering Committee
• Discussed during ICH SC meeting held in
Yokohama June 8-9, 2006
– Decided that since this is a US FDA requirement
a link from current Q&A to CDER website for
updated information was appropriate
Today’s Session
• Will share ISS and ISE analysis placement
tactics various sponsors have used
successfully and unsuccessfully
• Objective is to help you understand how
the information should be correctly
submitted in CTD/eCTD
• Information presented will be posted on
CDER website with link to current Q&A
Session 317—Medical Writing Track
• Background on CTD Efficacy and ISS/ISE
– Dr. Robert Temple
• Director, Medical Policy, CDER
• Overview of CTD Efficacy and ISS/ISE
– Dr. Armando Oliva
• Associate Director for Policy, Office of New Drugs, CDER
• eCTD Efficacy Submission Format
– Gary Gensinger
• Director, Regulatory Review Support Staff, Office of
Business Process Support, CDER
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.
CDISC v3 Submission Data Standards and Electronic CRTs
October 2, 2003
Rockville, Maryland
Future of Case Report Tabulation

Submissions
Randy Levin, M.D.
Director, Office of Information Management
1
Overview
• Study data standards
• Status of patient profile pilot
• Medical Review Technology for an NDA Safety Database
– Steve Gitterman, M.D., Ph.D., Deputy Director, Division of
Special Pathogens and Immunologic Drug Products
• Demo
– Steve Wilson, DrPH, Deputy Division Director, Division of
Biometrics II
• Study data submission transition milestones
• Q and A
– Norman Stockbridge, M.D., Ph.D., Deputy Director, Division of
CardioRenal Drug Products 2
What are Case Report
Tabulations?
• Study data
– Information collected during trials submitted to
the agency for evaluation
• Raw and derived data
• Multiple presentations
• Data definitions
– Information to understand the data
3
CRT Data Presentations
• Data tabulations datasets
– Each record includes a single observation for a subject
• Data listing datasets
– Each record includes a series of observations collected for a subject during
a study or for each visit during the study organized by domain
• Subject profiles
– PDF files that include all study data collected for an individual subject
organized by time
• Analysis datasets
– Records arranged to support a specific analysis not covered by other data
presentations (i.e., tabulations, listings or profiles)
4
Why Standards?
• Improve time to market for safe and effective treatments
(increased patient safety and reduced costs)
– Improve efficiency for clinical research
• Facilitates design and conduct of clinical trials
• Facilitates communication between researchers and study
sponsor (e.g., between CRO and drug company)
– Improves efficiency of evaluation of safety and efficacy
of investigational treatments
• Facilitates communication between regulatory authority and
applicant
• Facilitates development of efficient review environment (e.g.,
training, analysis tools)
5
Efficient Review Environment
• Standards provide:
– Common structure and terminology
– Single data source for review (less redundant
data)
• Standards allow:
– Use of common tools and techniques
– Common training
– Single validation of data
6
Study Data Standards
Goals
• Study data model
• Terminology and coding
• Content
7
Study Data Models
• HL7 Regulated Clinical Research
Information Management (RCRIM)
Technical Committee
– CDISC Submissions Data Domains Model
– Standard for Exchange of Nonclinical Data
(SEND)
– Annotated ECG waveform data
– Stability data
8
Terminology Standards
Initiatives
• Government
– FDA Data Council, HHS Data Council, CHI,
NCVHS
• Accredited Standards Development
Organizations
– HL7, ANSI, ISO
• Other
– ICH, CDISC, SEND consortium
9
Content Standards
• Indication specific guidance from individual
review divisions regarding specific data
collection recommendations
10
Patient Profile Pilot
• Evaluate
– Study data and data definition standard
– Use of standardized study data
• Current analysis and visualization tools
• PPD Informatics Patient Profiles
• Lincoln Technologies WebSDM
– Management of data
• WebSDM data validation, processing
• JANUS data repository model
11
Study Data and Data Definition
Standard
• CDISC Submission Domains Data Model
– FDA evaluated and commented on previous
CDISC versions
– CDISC version 3.1 being prepared for
presentation to RCRIM as informative standard
• Anticipate adoption of CDISC standard for
submission of study data and data definition
following approval by HL7
12
Use of Study Data
• PPD Patient Profiles
– Development of EasyView
• Allows reviewer to generate subject profile and
summary views of the data
• Allows sharing of techniques
• Uses standard study data and data definitions
– Anticipated implementation following approval
of CDISC standards by HL7 RCRIM
13
Use of Study Data
– Development
• Allows reviewers to
– Browse submitted datasets,
– Generate data tabulations and data listings presentations,
– Create summaries and reports
• Allows sharing of techniques
• Uses standard study data and data definitions
of CDISC standards by HL7 RCRIM 14
Management of Data
– Development
• Validation of data
• Parsing of data into database
of CDISC standards by HL7 RCRIM
• JANUS Data Repository
– Development
• Data model
15
• Implementation requirements
Medical Review Technology for an NDA Safety Database
Steve Gitterman, M.D., Ph.D., Deputy Director, Division of Special
Pathogens and Immunologic Drug Products
Demo
Steve Wilson, DrPH, Deputy Division Director, Division of Biometrics II
16
Study Data Submission
Transition Milestones
• Replace paper tables with electronic datasets
• Replace nonstandard datasets with standard
electronic datasets
• Replace data listings and patient profiles with
standard datasets and tools
• Replace SAS transport datasets with XML data files
• Add terminology and content standards
• Replace analysis datasets with standardized
communication of analysis methods and tools
17
Electronic Datasets
Electronic
Data Acrobat
Document Room
•Tabulations
•Data listings Stat/transfer
•Profiles Dataset files
•Analysis datasets
•Programs
•Definition
Submission Repository Review 18

Replace Subject Profiles
Electronic
Data Acrobat
Document Room
•Std Tabulations
•Programs
Profile
•Definition
Tools

Replace Data Listings
Electronic
Data Acrobat
Document Room
•Std Tabulations
•Programs Data Tables
•Definition
Profile
Data listing
Tools
Tabulations

Study Data Repository
Electronic
Data Acrobat
Document Room
•Std Tabulations
•Programs JANUS
•Definition Study Data
Repository Profile
Data listing
Tools
Tabulations

Replace Analysis Datasets
Data Electronic
•Std Tabulations Document Room
•Data listings
•Profiles
•Std analysis methods
•Definition JANUS
Study Data
Repository
Profile
Tools
Datasets

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.
Granularity Document
Annex to
M4: Organization of the CTD
Office of Training and Communication

5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573

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

October 2005
ICH
TABLE OF CONTENTS
INTRODUCTION......................................................................................................................... 1
ANNEX : GRANULARITY DOCUMENT ................................................................................ 2
Definition of a Document.............................................................................................................. 2
Module 2 .................................................................................................................................................. 3
Module 3 .................................................................................................................................................. 4
Module 4 .................................................................................................................................................. 6
Module 5 .................................................................................................................................................. 7
Document Pagination and Segregation....................................................................................... 8
Section Numbering Within Documents ...................................................................................... 8
Table of Contents Formatting...................................................................................................... 8
Module 2 .................................................................................................................................................. 8
Module 3 .................................................................................................................................................. 9
Module 4 .................................................................................................................................................. 9
Module 5 ................................................................................................................................................ 10
Granularity Document
Annex to M4: Organization of the CTD
You can use an alternative approach if that approach satisfies the requirements of the applicable statutes
INTRODUCTION
This is one in a series of guidances that provide recommendations for applicants preparing the
Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) for
submission to the U.S. Food and Drug Administration (FDA). This annex to the M4 guidance on
the organization of the CTD was developed by ICH in response to requests for additional
information after the harmonized CTD guidance documents were finalized in November 2000.
The annex is intended to clarify what constitutes a document in the paper CTD and in the eCTD,
and includes the following information for modules 2 through 5:
• location and hierararchy of headings within the modules

• document pagination and segregation
• section numbering within documents
• formatting of the table of contents
The information provided here reflects the consensus of the ICH parties. The annex will be
incorporated in FDA’s next revision of the M4 guidance.
1
This guidance was developed within the M4 CTD and M2 eCTD Implementation Working Groups of the
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH
process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process in
September 2002. A revision was signed off by ICH in November 2003, and the annex was corrected in Janaury
2004. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European
Union, Japan, and the United States.
1
ANNEX : GRANULARITY DOCUMENT
The CTD specifies many section headings and numbers. Could guidance be provided for
all modules on headings in relation to document location and the section headings within
those documents? Could guidance also be provided on where in the CTD and eCTD
multiple documents can be located in the hierarchy?
Could guidance be given on how documents should be paginated and on what the module
Table of Contents should therefore include?
Definition of a Document
A document is defined for a paper submission as a set of pages, numbered sequentially and
divided from other documents by a tab (see Document Pagination and Segregation section of this
Annex). A document can be equated to a file for an electronic submission. The granularity of
the paper and electronic submissions should be equivalent, although if a paper submission is
updated to be an electronic submission, some changes in granularity could be introduced to
facilitate on-going lifecycle management. In an electronic submission, a new file starts at the
same point at which, in a paper submission, a tab divides the documents.
In deciding whether one or more documents or files are appropriate, it should be considered that
once a particular approach has been adopted, the same approach should be used throughout the
life of the dossier since it is the intention that replacement documents/files be provided when
information is changed.
The following tables describe the levels in the CTD/eCTD hierarchy at which documents/files
should be placed and whether single or multiple documents are appropriate at each point. This
describes all sections of a CTD/eCTD, but for individual submissions, all sections might not be
applicable.
2
Module 2
Module 2 2.1 The TOC is only called for in the paper version of
the CTD; there is no entry needed for the eCTD
2.2
Note 1
2.3 Introduction
Note 2
2.3.S 2.3.S.1
2.3.S.2
2.3.S.3
2.3.S.4
2.3.S.5
2.3.S.6
2.3.S.7
Note 3
2.3.P 2.3.P.1
2.3.P.2
2.3.P.3
2.3.P.4
2.3.P.5
2.3.P.6
2.3.P.7
2.3.P.8
2.3.A 2.3.A.1
2.3.A.2
2.3.A.3
2.3.R
2.4
2.5
2.6 2.6.1
2.6.2
2.6.3
2.6.4
2.6.5
2.6.6
2.6.7
2.7 2.7.1
2.7.2
Note 4
2.7.3
2.7.4
2.7.5
2.7.6
Key
Documents rolled up to this level are not considered appropriate
One document may be submitted at this level
Note 1 : Optionality of granularity for the Quality Overall Summary is provided in order to
accommodate different levels of complexity of products. The applicant can choose the level at
which the QOS is managed.
Note 2 : One document should be submitted for each drug substance.
Note 3 : For a drug product supplied with reconstitution diluent(s), the information on the
diluent(s) should be provided in a separate part “P” document.
Note 4 : One document for each indication should be submitted, although closely
related indications can be within a single document.
3
Module 3
Note 1 3.1 The TOC is only called for in the paper version of the CTD;
Module 3
there is no entry needed for the eCTD
3.2 Note 2 3.2.S.1 3.2.S.1.1
3.2.S
3.2.S.1.2
3.2.S.1.3
3.2.S.2 3.2.S.2.1
3.2.S.2.2
3.2.S.2.3
3.2.S.2.4
3.2.S.2.5
3.2.S.2.6
3.2.S.3 3.2.S.3.1
3.2.S.3.2
3.2.S.4 3.2.S.4.1
3.2.S.4.2
3.2.S.4.3
3.2.S.4.4
3.2.S.4.5
3.2.S.5
3.2.S.6
3.2.S.7 3.2.S.7.1
3.2.S.7.2
3.2.S.7.3
Note 3 3.2.P.1
3.2.P
3.2.P.2 Note 4
3.2.P.2.1
Note 4
3.2.P.2.2
3.2.P.2.3
3.2.P.2.4
3.2.P.2.5
3.2.P.2.6
3.2.P.3 3.2.P.3.1
3.2.P.3.2
3.2.P.3.3
3.2.P.3.4
3.2.P.3.5
3.2.P.4 3.2.P.4.1
3.2.P.4.2
3.2.P.4.3
3.2.P.4.4
3.2.P.4.5
3.2.P.4.6
3.2.P.5 3.2.P.5.1
3.2.P.5.2
3.2.P.5.3
3.2.P.5.4
4
3.2.P.5.5
3.2.P.5.6
3.2.P.6
3.2.P.7
3.2.P.8 3.2.P.8.1
3.2.P.8.2
3.2.P.8.3
3.2.A 3.2.A.1
3.2.A.2
3.2.A.3
3.2.R Note 5
3.3 One file

Note 6
per reference
Key
One or multiple documents can be submitted at this level
Note 1 : In choosing the level of granularity for this Module, the applicant should consider that,
when relevant information is changed at any point in the product's lifecycle, replacements of
complete documents/files should be provided in the CTD and eCTD.
Note 2 : For a drug product containing more than one drug substance, the information requested
for part “S” should be provided in its entirety for each drug substance.
Note 3 : For a drug product supplied with reconstitution diluent(s), the information on the
diluent(s) should be provided in a separate part “P”, as appropriate.
Note 4 : The lower level of headings included in CTD-Q at this point are unlikely to be
individual documents or files.
Note 5 : Refer to regional guidances.
Note 6 : Literature References should be listed in the tables of contents.
5
Module 4
Module 4 4.1 The TOC is only called for in the paper version of the CTD; there
is no entry needed for the eCTD
Note 1
4.2 4.2.1 4.2.1.1 Studies
Note 1
4.2.1.2 Studies
Note 1
4.2.1.3 Studies
Note 1
4.2.1.4 Studies
Note 1
4.2.2 4.2.2.1 Studies
Note 1
4.2.2.2 Studies
Note 1
4.2.2.3 Studies
Note 1
4.2.2.4 Studies
Note 1
4.2.2.5 Studies
Note 1
4.2.2.6 Studies
Note 1
4.2.2.7 Studies
Note 1
4.2.3 4.2.3.1 Studies
Note 1
4.2.3.2 Studies
Note 1
4.2.3.3 4.2.3.3.1 Studies
Note 1
4.2.3.3.2 Studies
Note 1
4.2.3.4 4.2.3.4.1 Studies
Note 1
4.2.3.4.2 Studies
Note 1
4.2.3.4.3 Studies
Note 1
4.2.3.5 4.2.3.5.1 Studies
Note 1
4.2.3.5.2 Studies
Note 1
4.2.3.5.3 Studies
Note 1
4.2.3.5.4 Studies
Note 1
4.2.3.6 Studies
Note 1
4.2.3.7 4.2.3.7.1 Studies
Note 1
4.2.3.7.2 Studies
Note 1
4.2.3.7.3 Studies
Note 1
4.2.3.7.4 Studies
Note 1
4.2.3.7.5 Studies
Note 1
4.2.3.7.6 Studies
Note 1
4.2.3.7.7 Studies
4.3 One file per
Note 2
reference
Key
Note 1 : Typically, a single document should be provided for each study report included in
Module 4. However, where the study report is large, (e.g., a carcinogenicity study), the applicant
can choose to submit the report as more than one document. In this case, the text portion of the
report should be one document and the appendices can be one or more documents. In choosing
the level of granularity for these reports, the applicant should consider that, when relevant
information is changed at any point in the product's lifecycle, replacements of complete
documents/files should be provided.
Note 2 : Literature References should be listed in the tables of contents.
6
Module 5
Module 5 5.1 The TOC is only called for in the paper version of the CTD; there
is no entry needed for the eCTD
5.2
Note 1
5.3 5.3.1 5.3.1.1 Studies
Note 1
5.3.1.2 Studies
Note 1
5.3.1.3 Studies
Note 1
5.3.1.4 Studies
Note 1
5.3.2 5.3.2.1 Studies
Note 1
5.3.2.2 Studies
Note 1
5.3.2.3 Studies
Note 1
5.3.3 5.3.3.1 Studies
Note 1
5.3.3.2 Studies
Note 1
5.3.3.3 Studies
Note 1
5.3.3.4 Studies
Note 1
5.3.3.5 Studies
Note 1
5.3.4 5.3.4.1 Studies
Note 1
5.3.4.2 Studies
Note 2 Note 1
5.3.5 5.3.5.1 Studies
Note 1
5.3.5.2 Studies
Note 1
5.3.5.3 Studies
Note 1
5.3.5.4 Studies
5.3.6
Note 1
5.3.7 Studies
5.4 One file per
reference Note 3
Key
One document can be submitted at this level
Note 1 : The applicants should ordinarily provide the study reports as multiple documents (a
synopsis, a main body of the study report and appropriate appendices). Appendices should be
organized in accordance with the ICH E3 guideline, which describes the content and format of
the clinical study report. In choosing the level of granularity for reports the applicant should
consider that, when relevant information is changed at any point in the product's lifecycle,
replacements of complete documents/files should be provided.
Note 2 : For applications in support of more than one indication, this section should be repeated
for each indication.
Note 3 : Literature References should be listed in the tables of content.
7
Document Pagination and Segregation
Every document should be numbered starting at page one, except for individual literature
references, where the existing journal page numbering is considered sufficient. Applicants need
not display the number as '1 of n' where n is the total number of pages in the document.
Additionally, all pages of a document should include a unique header or footer that briefly
identifies its subject matter. In a paper-based drug submission, a similar identifier should be
used on a tab that precedes the document, to facilitate finding that document within the dossier.
An abbreviation of the full section number and title can be used.
If a section contains more than one document, a specific Table of Contents for that section can be
included to identify the chronology and titles of the documents contained therein, e.g.,
• Tab with “3.2.S.4.2 Analytical Procedures”
o Table of Contents, listing the title of Procedure A, Procedure B, Procedure
C
• Tab with “3.2.S.4.2 “Procedure A”;
o Procedure A (i.e. document, page 1-n)
• Tab with “3.2.S.4.2 “Procedure B”;
o Procedure B (i.e. document, page 1-n)
• Tab with “3.2.S.4.2 “Procedure C”;
o Procedure C (i.e. document, page 1-n)
If a section contains only a single document (e.g. 3.2.S.1.1 Nomenclature), only a tab identified
by “3.2.S.1.1 Nomenclature” should precede the document.
Section Numbering Within Documents
In order to avoid 5th, 6th, etc., level subheading numbering (e.g., 2.6.6.3.2.1) within a document,
the applicant can use a shortened numbering string. In this case, the document number and the
name (e.g., 2.6.6 Toxicology Written Summary) should appear in page headers or footers and
then section numbering within the document can be used, for example, 1, 1.1, 2, 3, 3.1, 3.2. Use
of the full numbering string (e.g., 2.6.6.3.2.1) is also considered acceptable.
Table of Contents Formatting
Module 2
The 2.1 CTD Table of Contents should go down to the third (e.g., 2.3.S) or fourth (e.g., 2.3.S.1)
level, depending on how a document is defined for the Quality Overall Summary. (See
Definition of a document for Module 2.)
8
Module 3
The Table of Contents provided under 3.1 should cover the high-level section numbering, the
associated section heading and the Volume number in the order that they appear in the drug
submission. This Table of Contents would be used to identify the contents of Module 3 as
defined in the M4Q guideline. It should go down to the fifth level only (e.g., 3.2.P.2.1). Note
that additional subsections and subheadings are defined in the M4Q guideline beyond this level
(e.g., under 3.2.P.2) and this formatting should be used within the dossier, despite not being
included in the 3.1 Table of Contents. The lower level Table of Contents described under
Document Pagination and Segregation should be excluded from the 3.1 Table of Contents.
At the applicant’s discretion, a Table of Contents can also be included for a particular section
that contains multiple documents, in order to identify the chronology and the document subject
matter. If there is a desire to introduce additional headers or subsection numbering beyond those
which are defined in the M4Q guideline, these should only be included within a document and
should be created neither as a separate document nor as a new subsection. In this case, a specific
Table of Contents for that document can be included to identify the chronology and titles of the
subsections contained therein. These documents and subsections should not appear in the 3.1
Table of Contents.
Furthermore, additional attachments or appendices should not be incorporated into this

formatting, except as a document under a section where multiple documents might be provided.
In this case, a cross-reference should be made within the relevant section to the attached or
appended document. If there is a desire to append or attach additional information to a section
that is comprised of only one document, this information should be incorporated within that
document.
All Table of Contents title entries should either correspond to heading names and section
numbering as defined in the M4Q guideline or to identifiers appearing on tabs (for a paper-based
drug submission only), preferably by their full title, which should easily identify any abbreviated
title that might be used on the corresponding tab. The Table of Contents should not specify any
page numbers.
Literature References should be listed in a Table of Contents specific for this section.
Module 4
The Table of Contents for Module 4 should include all of the numerical items listed in the CTD
guideline in order to identify all of the important components of the application (for example,
4.2.3.5.1 Fertility and early embryonic development) and should continue down to at least the
level of the study report. Thus, each study report should be identified in the table of contents.
The sections of a study report could be identified in the Module 4 Table of Contents of the
dossier or only in the Table of Contents of the individual study report.
9
Illustration of part of the Module 4 Table of Contents

4.2.3.2 Repeat-Dose Toxicity
Study aa-aaa: 30 day repeat dose toxicity study with Drug C in rat
Study bb-bbb: 6 month repeat dose toxicity study with Drug C in rat
Study cc-ccc: 30 day repeat dose toxicity study with Drug C in dog
Study dd-ddd: 6 month repeat dose toxicity study with Drug C in dog
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
Study ee-eee: Ames test with Drug C
etc.
Module 5
The Table of Contents for Module 5 should include all of the numerical items listed in the CTD
guideline in order to identify all of the important components of the application (for example,
5.3.5.1.1 Placebo Controlled Trials) and should continue down to at least the level of the clinical
study report. Thus each clinical study report should be identified in the table of contents. The
sections of a clinical study report (E3) could be identified in the Module 5 Table of Contents of
the dossier or only in the Table of Contents of the individual clinical study report.
Illustration of part of the Module 5 Table of Contents

5.3.5 Indication Z - Reports of Efficacy and Safety Studies
5.3.5.1 Indication Z - Study Reports of Controlled Clinical Trials Pertinent to the Claimed
Indication
5.3.5.1.1 Indication Z - Placebo Controlled Trials
Study xx-xxx: A double blind, placebo-controlled trial of Drug A in Indication Z
Study yy-yyy: A double blind……
5.3.5.1.2 Indication Z - Active Controlled Trials

Study zz-zzz: A double blind, active controlled trial of Drug A vs. Drug C in Indication
Z
5.3.5 Indication Q - Reports of Efficacy and Safety Studies

5.3.5.1 Indication Q - Study Reports of Controlled Clinical Trials Pertinent to the
Claimed Indication
etc.
10
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.




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<!ATTLIST ectd:ectd
xmlns:ectd CDATA #FIXED "http://www.ich.org/ectd"
>



<!ATTLIST leaf
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checksum-type CDATA #REQUIRED
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<!ATTLIST xref
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>
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>
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>
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<!ATTLIST m3-2-s-drug-substance
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>
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>
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>
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<!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-7-2-post-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
<!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*, m3-2-p-5-control-of-drug-product?, m3-2-p-6-
reference-standards-or-materials?, m3-2-p-7-container-closure-system?, m3-2-p-8-
stability?)>
<!ATTLIST m3-2-p-drug-product
%att;
>
<!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-critical-steps-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)*)>
<!ATTLIST m3-2-p-3-2-batch-formula
%att;
>
<!ELEMENT m3-2-p-3-3-description-of-manufacturing-process-and-process-controls
<!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-analytical-procedures?, 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
>
<!ATTLIST m3-2-p-4-1-specifications
%att;
>
<!ATTLIST m3-2-p-4-2-analytical-procedures
%att;
>
<!ATTLIST m3-2-p-4-3-validation-of-analytical-procedures
%att;
>
<!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-5-2-analytical-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;
>
<!ATTLIST m3-2-p-5-1-specifications
%att;
>
<!ATTLIST m3-2-p-5-2-analytical-procedures
%att;
>
<!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;
>
<!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-8-2-post-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
<!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-
adventitious-agents-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;
>
<!ELEMENT m3-2-a-2-adventitious-agents-safety-evaluation ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-2-adventitious-agents-safety-evaluation
%att;
>
<!ELEMENT m3-2-a-3-excipients ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-3-excipients
%att;
>
<!ATTLIST m3-2-r-regional-information
%att;
>
<!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?, m4-2-3-toxicology?)>
<!ATTLIST m4-2-study-reports
%att;
>
<!ELEMENT m4-2-1-pharmacology (leaf*, m4-2-1-1-primary-pharmacodynamics?, m4-
2-1-2-secondary-pharmacodynamics?, m4-2-1-3-safety-pharmacology?, m4-2-1-4-
pharmacodynamic-drug-interactions?)>
<!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?, m4-2-2-6-pharmacokinetic-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?)>
<!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-or-medium-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-early-embryonic-development?, m4-2-3-5-2-embryo-fetal-development?,
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function?, m4-2-3-
5-4-studies-in-which-the-offspring-juvenile-animals-are-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 | node-extension)*)>
<!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-further-evaluated ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-
or-further-evaluated
%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-
7-2-immunotoxicity?, 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;
>
<!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;
>
%att;
>
<!ELEMENT m5-clinical-study-reports (leaf*, m5-2-tabular-listing-of-all-clinical-
studies?, m5-3-clinical-study-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?, m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-
biomaterials?, m5-3-3-reports-of-human-pharmacokinetics-pk-studies?, m5-3-4-reports-
of-human-pharmacodynamics-pd-studies?, m5-3-5-reports-of-efficacy-and-safety-
studies*, m5-3-6-reports-of-postmarketing-experience?, m5-3-7-case-report-forms-and-
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-study-reports?, 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 | node-extension)*)>
<!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-drug-interaction-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)*)>
<!ATTLIST m5-3-2-1-plasma-protein-binding-study-reports
%att;
>
<!ELEMENT m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
<!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-pk-and-initial-tolerability-study-reports?, m5-3-3-2-patient-pk-and-
initial-tolerability-study-reports?, m5-3-3-3-intrinsic-factor-pk-study-reports?, m5-3-3-4-
extrinsic-factor-pk-study-reports?, m5-3-3-5-population-pk-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-subject-pd-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-controlled-clinical-studies-pertinent-to-the-claimed-indication?, m5-3-5-2-
study-reports-of-uncontrolled-clinical-studies?, m5-3-5-3-reports-of-analyses-of-data-
from-more-than-one-study?, m5-3-5-4-other-study-reports?)>
%att;
>
<!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)*)>
<!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-extension)*)>
<!ATTLIST m5-3-5-4-other-study-reports
%att;
>
<!ELEMENT m5-3-6-reports-of-postmarketing-experience ((leaf | node-extension)*)>
<!ATTLIST m5-3-6-reports-of-postmarketing-experience
%att;
>
<!ELEMENT m5-3-7-case-report-forms-and-individual-patient-listings ((leaf | node-
extension)*)>
<!ATTLIST m5-3-7-case-report-forms-and-individual-patient-listings
%att;
>
%att;
>
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 provides sample code for
the FDA draft eCTD Module 1 DTD version 2.01 hierarchy.



<!ELEMENT fda-regional:fda-regional (admin, m1-regional?)>
<!ATTLIST fda-regional:fda-regional
xmlns:fda-regional CDATA #FIXED "http://www.ich.org/fda"
>

<!ATTLIST leaf
ID ID #REQUIRED
checksum CDATA #IMPLIED
checksum-type CDATA #IMPLIED
>
<!ATTLIST title
ID ID #IMPLIED
>
<!ATTLIST link-text
ID ID #IMPLIED
>
<!ATTLIST xref
ID ID #IMPLIED
>
ID ID #IMPLIED
>

<!ATTLIST date
>
<!ATTLIST prod-name
>

<!ELEMENT application-information (submission)>
<!ATTLIST application-information
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)>

<!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;
>

<!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?)>
<!ATTLIST m1-1-forms
%att;
>
%att;
>
<!ELEMENT m1-1-2-fda-form-356h ((leaf | node-extension)*)>
<!ATTLIST m1-1-2-fda-form-356h
%att;
>
%att;
>
%att;
>
%att;
>
%att;
>

<!ELEMENT m1-2-cover-letters ((leaf | node-extension)*)>
<!ATTLIST m1-2-cover-letters
%att;
>

<!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*, 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;
>

<!ELEMENT m1-3-2-field-copy-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-2-field-copy-certification
%att;
>

<!ELEMENT m1-3-3-debarment-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-3-debarment-certification
%att;
>

<!ELEMENT m1-3-4-financial-certification-disclosure ((leaf | node-extension)*)>
<!ATTLIST m1-3-4-financial-certification-disclosure
%att;
>

<!ELEMENT m1-3-5-patent-exclusivity (m1-3-5-1-patent-information*,
m1-3-5-2-patent-certification*, 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;
>

<!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;
>

<!ELEMENT m1-5-application-status (m1-5-1-withdrawal-request*,
m1-5-2-inactivation-request*, 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;
>

<!ELEMENT m1-6-meetings (m1-6-1-meeting-request*,
m1-6-2-meeting-background-materials*,
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;
>
<!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;
>

<!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;
>

<!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)*)>
<!ATTLIST m1-8-3-stability-study
%att;
>

<!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
<!ATTLIST m1-9-6-other-correspondence-regarding-pediatric-exclusivity-study-plans
%att;
>

<!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
%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;
>

<!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;
>

<!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*,
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;
>
<!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;
>

<!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*, 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;
>
<!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;
>

<!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;
>
<!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;
>
<!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;
>

<!ELEMENT m1-15-promotional-material ((leaf | node-extension)*)>
<!ATTLIST m1-15-promotional-material
%att;
>

<!ELEMENT m1-16-risk-management-plans ((leaf | node-extension)*)>
<!ATTLIST m1-16-risk-management-plans
%att;
>
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 summary and integrated discussions of efficacy and safety and the
corresponding FDA regulations, where applicable, that inform the content of
those sections.
Placement of Integrated Summaries of Safety and Effectiveness (ISS/ISE) in
Applications Submitted in the eCTD Format
The CTD summary sections in Module 2 are not the correct location for the
integrated summaries of safety and effectiveness (ISS/ISE) required by 21 CFR
314.50 (see ICH M4: The CTD -- Efficacy Q&As, and presentations from the
2006 Drug Information Association Meeting).
CTD submissions are being submitted electronically, it is important that the

location of ISS/ISE information in an eCTD be consistent:
• In an eCTD, the ISE and ISS go in Module 5, section 5.3.5.3.

• If the narrative portions of the ISE and ISS are suitable for use in Module 2,
sections 2.7.3 and 2.7.4 of the CTD, the documents are placed once in these
sections and referenced in Module 5, section 5.3.5.3 (i.e., provide leaf elements in
section 5.3.5.3).
The following table lists the various sections of the CTD that contain summary
and integrated discussions of efficacy and safety and the corresponding FDA
regulations, where applicable, that inform the content of those sections. Any
questions about these matters can be raised with the appropriate reviewing
division at FDA.
CTD Section U.S. Regulation Comment
2.5 Clinical Overview
(~30 pages)
2.5.3 Overview of n/a Not a U.S.
Efficacy requirement, but
2.5.4 Overview of Safety recommended by
ICH guidance
2.7 Clinical Summary

(~50-400 pages)
2.7.3 Summary of 21 CFR 314.50 U.S. requirement for
Clinical Efficacy (c)(2)(viii) a Clinical Summary
2.7.4 Summary of
Clinical Safety
5.3 Clinical Study
Reports
5.3.5.3 Reports of 21 CFR 314.50 Integrated Summary
Analyses of Data from (d)(5)(v) of Efficacy
More than One Study 21 CFR 314.50 Integrated Summary
(Including Any Formal (d)(5)(vi) of Safety
Integrated Analyses,
Meta-Analyses, and
Bridging Analyses)
DIA Presentations
• Gensinger, Gary, MBA, Director, Regulatory Review Support Staff, Office of
Business Process Support; Standards and Successful Document Creation [PPT]
[PDF]
• Molzon, Justina, MS, Pharm, JD, Associate Director for International
Programs, FDA Center for Drug Evaluation and Research; ISS/ISE: Where Do
They Fit in the CTD/eCTD? [PPT] [PDF]
• Oliva, Armando, MD, Associate Director for Policy, FDA Office of New
Drugs; ISE/ISS Analyses: Clarity in a CTD or eCTD – Clinical Reviewer
Perspective [PPT] [PDF]
• Temple, Robert, MD, Associate Director for Medical Policy, FDA Center for
Drug Evaluation and Research; CTD – ISS/ISE Introduction and Summary of
Issues [PPT] [PDF]
SECTION 21
Portable Document
Format Specifications
● These specifications are for submitting documents in Portable Document Format
(PDF).
Portable Document Format Specifications
Revision History
2005-04-08 1.0 Initial version
Version 1.0 1
PORTABLE DOCUMENT FORMAT SPECIFICATIONS
These specifications are for submitting documents in Portable Document Format (PDF).
VERSION
Use PDF Version 1.4. PDF version 1.4 is for use with Adobe Acrobat 5.0 or higher1. No
additional software should be needed to read and navigate the PDF files.
FONTS
Embed fonts. PDF viewing software automatically substitutes a font to display text if the font
used to create the text is unavailable on the reviewer’s computer. In some cases, font
substitution can occur even when the fonts are available. For example, Helvetica or Times are
substituted even if available on the reviewer’s computer. Font substitution can affect a
document’s appearance and structure, and in some cases it can affect the information conveyed
by a document. Font availability is not guaranteed. Font availability to the reviewer is ensured
if all fonts are embedded. When fonts are embedded, all characters for the font should be
included not just a subset of the fonts being used in the document.
Limit fonts to those listed in Table 1. Font embedding does not always solve the problems that
occur when a reviewer tries to paste text from a PDF document into another software format. If
the font is not available on the reviewer’s computer, font substitution results even if the fonts are
embedded. This problem is avoided if the fonts are restricted to those listed in Table 1.
Table 1: List of Fonts

Font type Font name
San Serif AdobeSansMM (Adobe Sans Multiple Master)
Arial BolitaMT (Arial Bold Italic (From Monotype))
ArialBolMT (Arial Bold Monotype)
ArialtaMT Arial Italic (Monotype)
ArialMT Arial (Monotype)
Non proportional Couri (Courier)
CouriBol (Courier Bold)
CourriBolObl (Courier Bold Oblique)
Serif AdobeSerifMM (Adobe Serif Multiple Masters)
TimesNewRomPSBolitaMT (Times New Roman Bold
Italic)
TimesNewRomPSBolMT (Times New Roman Bold)
TimesNewRomPSItaMT (Times New Roman Italic)
TimesNewRomPSMT (Times New Roman)
1
It should be noted that Acrobat 6 and 7 use pdfa 1.4.
Version 1.0 2
TimesNewRoman
Other Symbo (Symbol)
ZapfDin (Zapf Dingbats)
Font size ranges from 9 to 12 points. Times New Roman, 12-point font is recommended for
reading narrative text. When choosing a point size for tables, a balance should be made between
providing sufficient information on a single page that may facilitate data comparisons while still
achieving a point size that remains legible. Generally, point sizes 9-10 are recommended for
tables; smaller point sizes should be avoided. Ten point fonts are recommended for footnotes.
Black is the recommended font color except that blue can be used for hypertext links. Light
colors do not print well on grayscale printers. The latter can be tested prior to submission by
printing sample pages from the document using a grayscale printer.
PAGE ORIENTATION
Save the page orientation for proper viewing and printing within the document. Proper page
orientation eliminates the need for reviewers to rotate pages. For example, setting page
orientation of landscape pages to landscape prior to saving the PDF document in final form
ensures a correct page presentation.
Page Size and Margins
Set up the print area for pages to fit on a sheet of paper that is 8.5 inches by 11 inches. A margin
of at least ¾ of an inch on the left side of page avoids obscuring information when pages are
subsequently printed and bound. Setting the margin for at least 3/8 of an inch on the other sides
is sufficient. For pages in landscape orientation, a 3/4 of an inch at the top allows more
information to be displayed legibly on the page. Header and footer information should appear
within these same margins (i.e., within 3/8 of an inch of the edge of the 8.5 by 11 inch page), so
the text will not be lost upon printing or being bound. These margins allow printing on A4 as
well. Oversized documents (e.g., CAD drawings) should be created to their actual page size.
SOURCE OF ELECTRONIC DOCUMENT
Avoid image based PDF files whenever possible. PDF documents created directly from an
electronic source such as a word processing file provides many advantages over PDF documents
created by scanning paper documents. Scanned documents are more difficult to read and do not
allow the reviewer to search or copy and paste text for editing in other documents.
METHODS FOR CREATING PDF DOCUMENTS AND IMAGES
Use the dpi settings in Table 2 for scanning documents. Scanned documents scanned at a
resolution of 300 dots per inch (dpi) ensure that the pages of the document are legible both on the
computer screen and when printed and, at the same time, minimize the file size. A resolution of
300 dots per inch (dpi) is recommended to balance legibility and file size. The use of grayscale
Version 1.0 3
and color significantly increases the file size and is used only when then these features improve
the reviewability of the material. After scanning, avoid resampling to a lower resolution. A
captured image should not be subjected to nonuniform scaling (i.e., sizing). See the following
table for resolutions for various images.
Table 2: Scanning Resolution

Document type Resolution
Handwritten notes 300 dpi (black ink)
Plotter output graphics 300 dpi
Photographs – black and white 600 dpi (8 bit gray scale)
Photographs - color 600 dpi (24 bit RGB)
Gels and karyotypes 600 dpi (8 bit grayscale depth)
High pressure liquid chromatography 300 dpi
IMAGE COMPRESSION TO REDUCE FILE SIZE
File compression methods include Zip/Flate and CCITT Group 4. File compression is a method
for reducing file size. Some methods of compression can result in loss of data and can introduce
compression artifacts that affect the reviewability of the information. The following two methods
provide lossless compression.
• Zip/Flate (one technique with two names) for lossless compression of color and grayscale
images is specified in Internet RFC 1950 and RFC 1951.
• CCITT Group 4 Fax compression technique recommendations for lossless compression

of black and white images is specified in T.6 (1988) - Facsimile coding schemes and
coding control functions for Group 4 facsimile apparatus.
IMAGE COLOR MATCHING
Because color varies from monitor to monitor, it is difficult to ensure that the reviewer will see
exactly the same color as in the actual image. However, for printing, there is more control over
the color by using CMYK (Cyan, Yellow, Magenta, Black) color model as opposed to the RGB
model. Pantone Matching using the color profile provided by CMYK ensure color consistency
for printing. The International Color Consortium (ICC) color profile specification is used when
PDF documents are printed.
PDF documents do not need embedded thumbnails.
HYPERTEXT LINKING AND BOOKMARKS IN TEXT AND TABLE OF CONTENTS
Hypertext links and bookmarks improve navigation through PDF documents. For text, 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 as the narrative
text are helpful to improve navigation efficiency. Hypertext links in text can be designated by
Version 1.0 4
rectangles using thin lines or by blue text. A consistent method in a document avoids confusion.
Relative paths when creating hypertext linking minimizes the loss of hyperlink functionality
when folders are moved between disk drives. Both absolute links that reference specific drives
and root directories do not work once the submission is loaded onto network servers are to be
avoided.
The document table of contents helps the reviewer navigate to the information of interest within
the document that is not provided in the submission table of contents. For documents with a table
of contents, bookmarks and hypertext links for each item listed in the table of contents including
all tables, figures, publications, other references, and appendices are essential for navigation
through documents. The use of invisible rectangles and blue text in the table of contents for
hypertext links avoids obscuring text. Other help for navigation includes a bookmark hierarchy
identical to the table of contents up to 4 levels in the hierarchy.
When creating bookmarks and hyperlinks, setting 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 helps with the review.
PAGE NUMBERING
In general, it is easier to navigate through an electronic document if the page numbers for the
document and the PDF file are the same with the initial page of the document numbered as page
one. There is an exception when a document is split because of its size (e.g., > 100 MB) and the
second or subsequent file is numbered consecutively to that of the first or preceding file.
OPEN DIALOG BOX
Set the initial view of the PDF files to Bookmarks and Page. The open dialog box sets the
document view when the file is opened. Set the initial view of the PDF files to Bookmarks and
Page to help with the ease of review. If there are no bookmarks, the initial view is set as Page
only. Magnification and Page Layout is set to default.
NAMING PDF FILES
Use lower case characters and avoid using special characters except hyphens in file names.
Special characters to avoid include punctuation, underscore, spaces, or other nonalphanumeric
symbols (e.g., \ / : * ? < > | “ % # +) . See other specifications for name length limitations.
Version 1.0 5
SECTION 22
Specification for Transmitting

● This document provides specification for transmitting electronic submissions
using eCTD specifications. Details are included for transmitting the electronic
submission on physical media or electronically.
Specification for Transmitting Electronic Submissions using eCTD Specifications
Revision History
2005-06-14 1.1 Correction of typographical error in Type of Media table
1
Specifications 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.
I. PHYSICAL MEDIA
A. Address for electronic submissions on physical media
CBER

Document Control Center, HFM-99
1401 Rockville Pike
Rockville, MD 20832-1448
CDER

Central Document Room
5901-B Ammendale Rd.
Beltsville, Md. 20705-1266
B. Type of media
See the following table:
Type of media Format Size

Floppy Disk 3.5 inch 1.44 MB Up to 14.4 MB (10 disks)
CD ROM CD-R Joliet Specification Up to 3 GB (1- 5 CDs)
DVD DVD-RAM Up to 45 GB (1 to 6 DVDs)
DVD-R
DVD+R
DVD+/-R
Digital Linear Tape 35/70 or 40/80 DLT tapes No limit
using
• Veritas backup exec,
• Win2000 native backup.
do not use compression
Linear Tape Open LTO 1 (100/200 GB) or LTO No limit
2
2 (200/400 GB)tapes using

• Veritas backup exec
• Win2000 native
backup
uncompressed
C. Media preparation
Send all electronic media adequately secured in a standard binder marked clearly on the outside
ELECTRONIC REGULATORY SUBMISSION FOR ARCHIVE. The following information
should be included on the media labels:
Sponsor, applicant or company name
Name of the product, chemical or ingredient
Appropriate regulatory ID number (e.g., IND number)
Submission date (dd-mmm-yyyy)
Media series (e.g., “1 of 1”, “1 of 2”
II. ELECTRONIC TRANSMISSION
FDA is currently working on updating its capabilities to receive submissions electronically.

Contact the appropriate centers for details on alternatives for sending in electronic submissions.
3
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 analysis — 5.3.5.3 reports of analyses of data from
more than one study — Module 5 provides necessary organization
structures through STF.
o Module 2 Summaries — critical and concise summaries —page counts do
not define what’s acceptable.
Standards and
Successful Document
Creation
Director, Regulatory Review Support
Staff
Office of Business Process Support
Center for Drug Evaluation and
Research
Why are we here?
• ISS/ISE placement one of the most frequently
asked questions
• ISS/ISE Represent Analysis
– 5.3.5.3 Reports of analyses of data from more than
one study
– Module 5 provides necessary organization structures
through STF
• Module 2 Summaries
– Critical and Concise Summaries
– Page count do not define what’s acceptable
The Importance of Standards
• FDA Presentation in June of 2002
http://www.fda.gov/cder/regulatory/ersr/2002_0-6_19_standards/index.htm
• Critical if FDA is to modernize the review

process
• Critical to building more collaborative review
processes
– caBIG https://cabig.nci.nih.gov
• Critical to improving reviewer efficiency and
effectiveness through repeatability
• Not limited to Drug/Biologic Review Processes
Practical Document Standards
• Enhances the reviewer’s experience
• Decreased inter-application variability
• Decreases reviewer ramp up time
• Allows industry to develop standard
templates
Remember!
• One of your goals is communication
– Clarity improves reviewability
– Consider application from reviewer’s
standpoint
– Create document level Tables of Content with
appropriate bookmarks
– Use clear concise leaf titles
Provide Bookmarks
with Intuitive Names
• Good • Bad
Bookmarks
• Useful to have a bookmarks back to higher
levels of the submission
Clear Concise Leaf Titles
ISS/ISE Experiences
• Documents are varied
– Application A
• 2.7.3 70 pages
• 2.7.4 86 pages
– Application B
• 2.7.3 697 pages
• 2.7.4 904 pages
– Application C
• 2.7.3 3,519 pages
• 2,7,4 10,469 pages
Most Egregious Examples
• Page count in excess of 20,000
• Scanned document
• No table of contents
• Bad bookmarks
Contact Information
• Electronic Submission Questions
esub@cder.fda.gov
• SDTM Questions
cder-edata@cder.fda.gov
• Gary Gensinger
gary.gensinger@fda.hhs.gov
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.
503
Study Tagging File Workshop
February 26, 2004

US Food and Drug Administration
Rockville, MD
504
The Backdrop
• NDAs will have multiple submissions over their life-cycle
– The 10 most active eNDAs ranged from 76 to 202 electronic
submissions:
• 6 had 111 to 139 submissions
• 1 had 185 submissions
• 1 had 202 submissions
• NDA submissions contain thousands of files in a single
submission
– One initial submission in FY 2003 had 5478 files
– One eCTD submission in FY 2004 had over 15000 files in a
supplement
• Typically the majority of files are Study Report Files such as Case
Report Forms (CRFs) and Case Report Tabulations (CRT)
associated with multiple Study Reports
505
Problems
• Computer system limitations
– A maximium of 256 characters 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
– Computer Displays can not readily display lengthy
path and filenames.
• In many cases some filenames could be the same up to very
ending making it difficult for reviewers
506
File System Display - Shortcomings
507
File System Display - Shortcomings
508
Or even - for those who prefer the icon view
509
A Better Way to Display
510
Study Report Challenges

• The ICH CTD E3 granularity document includes 25 sections for data to be
submitted for each study in the application
– Individual headings for each section are not included in the eCTD DTD
• The E3 granularity document includes ICH recognized Type of Control,

Species, and Route of Administration categories
– The globally acknowledged values are not included in the eCTD DTD
• The ICH CTD recommends smaller granular files instead of single large files
encompassing all aspects of the study report
– Changes can be made to individual sections of the study
• Reviewers only need to concentrate on the changed portion
• Each section can result in the creation of one or more files containing
pertinent information
– Multiple Case Report Forms (CRFs) from multiple sites
– Multiple Case Report Datasets from multiple sites
511
Interim Fix
• Several proposals between July 2002 and
March 2003
– Including in the eCTD DTD
– Separate DTD with values included as
elements/attributes
– Separate DTD using the values as “tags” without
validation
• ICH agreement in July 2003 Brussels
– Use separate DTD with values as “tags” with deferred
validation by a stylesheet
512
Type of Study Report Tags

• Overall Study Report Document Identifier and
Category Tags
– Study Report Title
– Study Report ID
– Species
– Route of Administration
– Types of Control
• Granular Study Report File Property Tags

– E3 granularity sections
513
Tags for Overall Study Report

• Species for Study • Routes of
– mouse Administration
– rat – oral
– rabbit – intravenous
– other-rodent – intramuscular
– dog – intraperitoneal
– nonhuman-primate – subcutaneous
– other-nonrodent- – inhalation
mammal – topical
– nonmammal
514
Tags for Overall Study Report

• Controls used during the study
– placebo
– no-treatment-control
– dose-response-without-control
– active-control-without-placebo
– external-control
515
Granular Study Report File Tags

E3 Granularity Section Tags
– synopsis
– study-report-body
– protocol-or-amendment
– sample-case-report-form
– iec-erb-consent-form-list
– list-description-investigator-site
See others defined in the Guidance
516
Overall Study Report Category
Tags
Study Report
Mouse oral
placebo
Synopsis file
Report Body file
Protocols file Rat no-
intravenous
treatment
Case Report
-control
Form files
Data Tabulation
files
dose-response-
without- topical Rabbit
control
517
Granular Study Report File Tags

synopsis
Study Report
Mouse Study
StudyReport
Report
study-report-body
Synopsis file
Report Body file protocol-or-amendment
intravenous Protocols file
case-report-forms
CRF 1 Site 1 site 1
CRF n Site n
case-report-forms
Data File 1 site n
dose-response- Data File 2
without-
data-tabulation-dataset
control
518
What is a Study Tagging File

Study Tagging File
Full Title of the Study Report Document Id
dose-response-
Mouse intravenous without-
control
synopsis study-report-body protocol-or-amendment
case-report-forms data-tabulation-dataset
site 1
case-report-forms
site n
519
Study Report Files and Study
Tagging File
Leaf B
Leaf
Synopsis.pdf A
Body of Report .pdf
Leaf C
Leaf
Protocol.pdf K
CRF.pdf
B
Leaf
O Leaf
CRF.pdf
N dataset.XPT
Leaf E Leaf
dataset.XPT Stf-study-report.xml
520
Building a STF XML file

521
Workshop Sample
999999/
0000/
m5/
53-clin-study-report/
535-rep-effic-safety-study/
Claimed indication/
5351-study-report-contrib/
xxx394-90-04/
522
Workshop Sample
• Files in Study Report Folder
– XXX394-90-04synopsis.pdf
• ../../../../../../index.xml#ID350438
– XXX394-90-04body-of-report.pdf
• ../../../../../../index.xml#ID350438a
– XXX394-90-04protocol.pdf
• ../../../../../../index.xml#ID350438b
– CRF1site01.pdf
• ../../../../../../index.xml#ID820214
– CRFnsiten.pdf
• ../../../../../../index.xml#ID387525
– Dataset1.xpt
• ../../../../../../index.xml#ID246080
– Dataset2.xpt
• ../../../../../../index.xml#ID382213
523
Build the STF File

Start with the XML headers and Root
Element

<?xml-stylesheet type="text/xsl"
href="../../../util/style/ich-stf-stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM “../../../util/dtd/ich-stf.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-
version=“2.0" xmlns:xlink="http://www.w3c.org/1999/xlink">
Note: ../../../ means to use the relative location of the STF file
524
Build the STF File -2

<document-identifier>
<title> A Parallel Group, Placebo-
Controlled, Modified Double-Blind, Dose-
Ranging Study with XXX 394 in Patients with
SLE S107</title>
<doc-id>S107</doc-id>
<category name=”type-of-control”
info-type=”ich-e3” >placebo</category>
</document-identifier>
525
Build the STF File - 3

• Add the tags for the study report synopsis
<document>
<doc-content >
<property name="leaf-id" info-type=”fda”>
../../../../../../index.xml#ID350438
</property>
<file-tag name="synopsis”
info-type=”ich-e3”/>
</doc-content>
526

• Add the tags for the body of the study report
<doc-content >
../../../../../../index.xml#ID350438a
</property>
<file-tag name="study-report-body“
</doc-content>
527

• Add the tags for the CRF forms
<doc-content >
../../../../../../index.xml#ID820214
</property>
<property name=”site-identifier”
info-type=”fda”>1</property>
<file-tag name="case-report-forms“
</doc-content>
528

• Add the tags for the CRF forms
<doc-content >
../../../../../../index.xml#ID387525
</property>
<property name=”site-identifier”
info-type=”fda”>n</property>
<file-tag name="case-report-forms“
</doc-content>
529

• Add the tags for the analysis datasets and close the STF
File
<doc-content >
../../../../../../index.xml#ID246080
</property>
<file-tag name="analysis-dataset“
</doc-content>
</document>
</ectd:study>
530
Displaying STF Files

531
Types of Study Reports

• 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
• 4.2.4.1 Long term [carcinogenicity] studies
– grouped by species
• 5.3.5.1 Study reports and related information of
controlled clinical studies pertinent to the claimed
indication
– grouped by type of control
532
First Attempts to Display The Study File Tags
533
Order of Display
• The Comprehensive Table of Contents
Headings and Hierarchy
– Non-clinical Study Reports
• 4.2.1.1 Primary pharmacodynamics
– Clinical Study Reports
• 5.3.1.1 Bioavailability (BA) Study reports
• http://www.fda.gov/cder/regulatory/ersr/ectd.htm
534
Clinical
Concept
Clinical Study Reports
Reports of Efficacy and Safety Studies
Study Reports of Controlled Clinical Studies Pertinent to Claimed
Indication
Controlled : type-of-control – placebo
doc-id xxx394-90-04 : title - A Parallel Group, Placebo-
Controlled, Modified Double-Blind, Dose-Ranging Study
with XXX 394 in Patients with SLE
Synopsis
synopsis – leaf-id ../../../../../../index.xml#ID350438
Note: the above is defined to mean group the study files under the
heading “Controlled” based on the value “placebo” of the type-of-
control tag. Show the value of the doc-id tag with the value of the title
tag from the STF XML file. Create the heading “Synopsis” based on
the synopsis tag. Display the title of the synopsis file as a hyper-link
using the title and xlink:href values in the index.xml pointed to by the
leaf-id tag value in the STF XML file.
535
Concept - 2
Study Report
study-report-body – leaf-id ../../../../../../index.xml#ID350438a
Protocol and amendments
protocol-or-amendment – leaf-id
../../../../../../index.xml#ID350438b
Documentation of Statistical Methods and Interim Analysis Plans
statistical-methods-interim-analysis-plan – leaf-id
../../../../../../index.xml#ID350438c
Demographic Data
demographic-data - leaf-id ../../../../../../index.xml#ID350438d
Adverse Event Listings
adverse-event-listings – leaf-id
../../../../../../index.xml#ID350438e
536
Concept - 3
Case Report Forms
Site : site-identifier – 01
Note: Use the value provided in the STF file for “01”
Could be any meaningful value to your client such as
Hawaii, X-123, London Site 15, etc.
case-report-forms – leaf-id ../../../../../../index.xml#ID820214

Site : site-identifier – 02
537
Concept - 4
Data Tabulation
data-tabulation – leaf-id ../../../../../../index.xml#ID246080
Data Definitions
tabulation-definition leaf-id ../../../../../../index.xml#ID861459
538
Concept - 5
Analysis Datasets
Analysis Datasets
analysis – leaf-id <example for display>
analysis – leaf-id <example for display>
Analysis Programs
analysis-program – leaf-id <example for display>
analysis-program – leaf-id <example for display>
Data Definitions
analysis-definition – leaf-id <example for display>
Annotated CRF
annotated-CRF - leaf-id ../../../../../../index.xml#ID776509
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.
Page 1
Transformation of the backbone from XML to HTML

<?xml version="1.0" encoding="iso-8859-1" standalone="no" ?>

- <xsl:stylesheet version="1.0" xmlns:xsl="http://www.w3.org/1999/XSL/Transform"
xmlns:ectd="http://www.ich.org/ectd" xmlns:xlink="http://www.w3c.org/1999/xlink">
- <xsl:template match="/">
- <html>
- <head>
<link rel="stylesheet" href="util/style/screen.css" type="text/css"
media="screen" />
</head>
- <body>
- <h2>
eCTD
- <font size="-1">
DTD version
<xsl:value-of select="/ectd:ectd/@dtd-version" />
</font>
</h2>
<xsl:apply-templates select="/ectd:ectd/*" />
</body>
</html>
</xsl:template>
- <xsl:template match="*">
- <ul type="square">
- <li>
<xsl:value-of select="name()" />
- <font color="green">
- <xsl:if test="@manufacturer != ''">
[manufacturer:
<xsl:value-of select="@manufacturer" />
]
</xsl:if>
- <xsl:if test="@substance != ''">
[substance:
<xsl:value-of select="@substance" />
]
</xsl:if>
- <xsl:if test="@product-name != ''">
[product name:
<xsl:value-of select="@product-name" />
]
</xsl:if>
- <xsl:if test="@dosageform != ''">
[dosage form:
<xsl:value-of select="@dosageform" />
]
</xsl:if>
- <xsl:if test="@indication != ''">
[indication:
<xsl:value-of select="@indication" />
]
</xsl:if>
- <xsl:if test="@excipient != ''">
[excipient: Page 2
<xsl:value-of select="@excipient" />
]
</xsl:if>
</font>
</li>
<xsl:apply-templates />
</ul>
</xsl:template>
- <xsl:template match="leaf">
- <li>
- <xsl:element name="a">
- <xsl:attribute name="href">
<xsl:value-of select="@xlink:href" />
</xsl:attribute>
<xsl:value-of select="title" />
</xsl:element>
- <font color="red">
[
<xsl:value-of select="@operation" />
]
</font>
</li>
</ul>
</xsl:template>
- <xsl:template match="node-extension">
- <li>
<xsl:value-of select="title" />
<xsl:apply-templates select="leaf|node-extension" />
</li>
</ul>
</xsl:template>
</xsl:stylesheet>
file://E:\dl\ectd-2-0.xsl 2/6/2007
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).
Rockville, Maryland 20857
Presents…
NDA Electronic Data Analysis Training

NEDAT
Contents
INTRODUCTION .............................................................................................................1
Prerequisites ..................................................................................................................1
LESSON 1 – NEDAT PRESENTATION ..........................................................................3
LESSON 2 - ACCESSING ELECTRONIC DATA ............................................................9

Electronic Document Room (EDR).................................................................................10
Associating Files ..........................................................................................................13
About The SAS System Viewer ..................................................................................14
Installing The SAS System Viewer .............................................................................15
Launching The SAS System Viewer...........................................................................15
Navigating SAS Transport Files .................................................................................16
Selecting Cells .............................................................................................................17
Sorting Datasets.........................................................................................................17
Sorting Using Query Language ..................................................................................18
Searching (Find) Text.................................................................................................19
Map a Network Drive..................................................................................................20
Copying Files or Folders to Your Computer................................................................21
Review ........................................................................................................................25
LESSON 3 - CONVERSION AND ANALYSIS TOOLS ................................................27

About StatTransfer V5 ..................................................................................................28
Launching StatTransfer .................................................................................................28
StatTransfer Dialog Boxes .............................................................................................29
MS Excel Conversion....................................................................................................29
About Microsoft Excel ..................................................................................................31

Open MS Excel Worksheet ............................................................................................31
MS Excel Features........................................................................................................32
Microsoft Access Conversion.........................................................................................33
About Microsoft Access ................................................................................................34
MS Access Features......................................................................................................36
Review ........................................................................................................................39
LESSON 4 – JMP FEATURES .....................................................................................41

About JMP...................................................................................................................42
Launch JMP.................................................................................................................42
Import a SAS Transport File ..........................................................................................43
Navigating a JMP Dataset..............................................................................................45
Selecting Cells .............................................................................................................45
Move and Hide Columns ...............................................................................................46
Column Headers ...........................................................................................................48
Saving a JMP File.........................................................................................................49
Review ........................................................................................................................51
LESSON 5 – JMP TOOLS ............................................................................................53

Sort Command ...........................................................................................................54
Select Rows "Where…" ................................................................................................54
Subset .........................................................................................................................55
Search Command..........................................................................................................56
Group Summary ...........................................................................................................57
Distribution of Y ..........................................................................................................58
Exclude/Include............................................................................................................59
Adding a Computed Column ..........................................................................................61
Fit Y by X....................................................................................................................62
Exporting to Excel and Word .........................................................................................65

Review ........................................................................................................................69
LESSON 6 – SUPPORT................................................................................................71
Classes and Documentation ...........................................................................................72
Additional Training ......................................................................................................73
Help Menus .................................................................................................................74
OIT Support.................................................................................................................74
Peer Support ................................................................................................................74

Introduction
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).
NEDAT provides the information necessary to get you started on reviewing electronic datasets.
The course includes instructions on how to access the data via the Electronic Document Room
(EDR) and convert the files to formats that can be used with a variety of software packages,
including MS Excel and Access. The course also offers an introduction in The SAS System
Viewer and JMP to open datasets and perform some basic data analyses. Instruction is provided
for exporting statistical information to other applications for Word processing and additional
analytical review.
The NEDAT program does not end with in-class instruction. The final lesson includes support
options for reviewers who have taken the class, but require access to additional technical support.
NEDAT incorporates the use of an extensive classroom manual, desktop reference guides, and
software online guides for on-hand desktop support. The course also instructs reviewers how to
access support via OIT and peers within the Center and provides a glossary of NEDAT terms.
Prerequisites
Before beginning these lessons, you should have a working knowledge of Windows 95 and its
conventions. In particular, you should know how to do the following:
• Use a mouse and standard Windows or Macintosh menus and commands.
• Open, save, and close files.
• Resize and position application and document windows on the screen.
For help with any of these techniques, please see your Windows 95 documentation or the CDER
OIT Help Desk. Classes in Windows 95 are offered by OIT.
NDA Electronic Data Analysis Training – Introduction 1

Windows 95 System requirements:
• Windows 95
• 486 or higher processor with VGA or higher monitor
• 191 MB available disk space for software
• 12 MB RAM
Windows NT 4.0 and later:

• Version 4.0 or higher
• 486 or higher processor with VGA or higher monitor
• 191 MB available disk space for software
• 16 MB RAM
2 NDA Electronic Data Analysis Training – Introduction

Lesson 1 – NEDAT
Presentation
Please use the blank lines to take notes during the presentation.
This lesson will take approximately 10 minutes to complete.
NDA Electronic Data Analysis Training – Lesson 1: NEDAT Presentation 3

Slide 1 ____________________________
NDA Electronic Data Analysis
Training (NEDAT) ____________________________
____________________________
CDER/OIT Training
____________________________
____________________________
Please Sign-In Before Seating and
Make Sure to Logon with Your ____________________________
Username
____________________________
____________________________
_____________________
Slide 2 ____________________________
NEDAT Overview
____________________________
❚ Review of “Providing Regulatory
Submissions in Electronic Format - NDAs” ____________________________
Guidance
❚ SAS Transport ____________________________
❚ Blueprint of Guidance
____________________________
❚ NEDAT Objectives
____________________________
____________________________
____________________________
_____________________
4 NDA Electronic Data Analysis Training – Lesson 1: NEDAT Presentation

Slide 3 ____________________________
CDER ERSR Goals for 2002
____________________________
❚ All submissions can be received and
archived electronically ____________________________
❚ All electronic submissions, reviews, and
other related data can be accessed by the ____________________________
reviewer through a desktop computer
❚ Data analysis
____________________________
❚ Publicly available information is on the ____________________________
Internet
____________________________
____________________________
_____________________
Slide 4 ____________________________
SAS Transport File (STX)
____________________________
❚ Flexible format - compatible with multiple ____________________________
formats (SAS, JMP, Access, etc.)
❚ Archivable ____________________________
❚ defacto Standard
❚ Free viewer (The SAS System Viewer) ____________________________
❚ User-friendly navigation
____________________________
____________________________
____________________________
_____________________
Slide 5 ____________________________
NDA Discipline Folder:
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
_____________________

Slide 6 ____________________________
Each Datasets folder contains
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
_____________________
Slide 7 ____________________________
Each Study Folder Contains:
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
_____________________
Slide 8 Each SAS Transport File is ____________________________

Formatted:
____________________________
❚ Table/Spreadsheet Format ____________________________
❚ Columns Headers Contain Variable ____________________________
❙ Abbreviated labels for each set of
column data ____________________________
____________________________
____________________________
____________________________
_____________________
6 NDA Electronic Data Analysis Training – Lesson 1: NEDAT Presentation

Slide 9 ____________________________
Incoming Electronic Data
____________________________
Open in
SAS
____________________________
Electronic NDA
Open in
SAS Viewer Desktop
____________________________
SAS Transport
Import in JMP
____________________________
Stat/Transfer
Access/Excel ____________________________
Other
____________________________
____________________________
_____________________
Slide 10 ____________________________
NEDAT Objectives
____________________________
❚ NDAs accessed via EDR
____________________________
❚ The SAS System Viewer to open, navigate,
sort, and search SAS Transport files
____________________________
❚ Use Stat/Transfer to convert files to MS Excel
and Access
____________________________
❚ JMP to import, navigate, search, and perform
basic statistical analysis
____________________________
❚ Support Options
____________________________
____________________________
_____________________
Slide 11 ____________________________
NDA Electronic Data Analysis
Training (NEDAT) ____________________________
____________________________
Let’s begin the NDA
Electronic Data ____________________________
Analysis Training.…..
____________________________
____________________________
____________________________
____________________________
_____________________

Lesson 2 - Accessing
Electronic Data
Electronic data, currently in SAS Transport file format, submitted to CDER’s Central Document
Room (CDR) is placed on the CDER network for access and review by CDER staff. Before
these datasets can be reviewed, staff must first be able to access an NDA folder via the
Electronic Document Room (EDR) and save a drive path (map) to the submission folder. This
lesson will cover how to search for a specific NDA via the EDR Intranet site. Once the drive
path to the NDA data folder is found on the network, The SAS System Viewer is used to open,
view, and perform basic analysis on the data. The path to the folder can then be saved and
assigned a drive letter (mapping), where the datasets can then accessed or converted to a software
package most conducive to review staff needs.
Windows 95 file management tools, Microsoft’s Internet Explorer, Adobe Acrobat, and The SAS
System Viewer are used to complete the tasks in this chapter.
This lesson will take about 30 minutes to complete.
NDA Electronic Data Analysis Training – Lesson 2: Accessing Electronic Data 9

Electronic Document Room (EDR)
Once an NDA, Amendment, or Supplement has been placed on the CDER network, the location
of the datasets can be found via the Electronic Document Room (EDR). The EDR is a Web
based tool on the CDER network that contains search capabilities for NDAs and their associated
Amendments and Supplements. Once you have an NDA number, use the EDR to find the
location of the submission files.
To access the EDR:
! Start MS Internet Explorer by double-clicking the icon on the Win95 desktop
! In the Address field, type EDR and press [ENTER]
The Electronic Document Room Web page will appear.
! In the NDA Quick Search field, remove the 0, enter the sample classroom NDA number,
123456 (Actual NDAs begin with 0) and press the Search button
Address
Field
NDA Search
If the NDA number is valid, the NDA Application #, Trade Name, and Company Name will
appear for each submission. Type, Sequence #, Sup. Mod. Type, Stamp Date, Application Drive
Path (location on the network), and Comments will appear for the NDA and any associated
Amendments or Supplements. Note the sample NDA drive path
(\\cds006\samplenda\n123456), as it will be used in the next section.
10 NDA Electronic Data Analysis Training – Lesson 2: Accessing Electronic Data

NOTE: NDA, Amendment, and Supplement folders may look identical on the network. Use the
EDR to distinguish between them.
NDA
Amendment
To access and display the contents of the main NDA folder, click on Select to view Document
for the respective NDA, Amendment or Supplement. The next window will display a list of
folders and files contained in the electronic NDA.
Submission
Contents
Submission
Location
! Double-click the crt folder. The datasets are contained in the folder datasets.
In the datasets folder, there is a file datatoc.pdf. This file is a table of contents for all of the data
in the crt folder. To access the dataset table of the contents, double-click directly on the
datatoc.pdf file in the EDR window.

If installed, Adobe Acrobat or Reader will launch with the datatoc.pdf in the main window. The
PDF file lists all of the folders that contain datasets for this sample submission. The datasets
used in NEDAT are located in Phase 3 Controlled Studies, in the Study number, 09, folder.
! To access these files, click on the Study 09 link in datatoc.pdf. This link points to a file,
define.pdf, in the Study 09 folder that file contains a list of all the datasets in the study.
The first page of the file is the table of contents. Links are established in the table that will
allow you to open the file or the data definition table for each dataset by clicking on the
corresponding links.
Link to Data Link to SAS

Definition Transport

To get a better idea of how the variables appear in column header, go back to the first page of the
PDF file. As stated, the dataset table of contents contains links to the actual datasets.
! Click on the link for the lab1.xpt file
Lab1.xpt link
Adobe Acrobat will prompt you to confirm that The SAS System Viewer will launch when you
click on this link.
! Click the Yes button to open the dataset. If you do not receive this message, perform the
steps listed in Associating File Types.
Associating Files
Windows 95 gives you the ability to launch applications by opening an associated file from one
of the Windows file management screens. In order to perform this, Windows 95 must have a
relationship, or association, established between a file type and an application. For example,
after installing MS Word, Windows is setup to open Word by clicking on any file that ends in a
.DOC extension.
If you click on a file and are prompted by Win95 with an Open With window, then the
association of that file type with an application has not been setup in Windows. If this situation
happens after installing The SAS System Viewer, perform the following procedure:
Note: Not all file types can be associated. Make sure you are using the correct software before
performing these steps
1. If the Open With window appears when clicking on files
• Click on The SAS System Viewer icon, labeled SV, from the list of programs
• If the icon does not appear, click the Other button and navigate to C\:PROGRAM
FILES\SAS SYSTEM VIEWER\SV.EXE
• Click the OK button. The SAS System Viewer This will open automatically when you click
on an associated file

2. Associating Files from My Computer1
• Double-click My Computer
• On the View menu, click Options, and then click the File Types tab
• To create a new file type, click New Type. To modify the settings for an existing file
type, click the type, and then click Edit
• Specify a description for the file type and the filename extension associated with this
type of file
• Click New to define an action for this file type. If you are modifying an existing type,
you can click the command in the Action box that you want to modify, and then click
Edit
• Specify the action that you want to define, such as Open or Print, and the command that
should run to complete this action
• Repeat the previous two steps for as many actions as you want to define for this file type
Once the file type .XPT has been associated with The SAS System Viewer, you can proceed to
the next section of this lesson
About The SAS System Viewer

The SAS System Viewer is a free statistical software application that allows viewing files
created by the SAS System. The SAS System Viewer displays datasets in a grid format.
The SAS System Viewer has the following capabilities (NEDAT topics in bold):
• View SAS Datasets • Create new SAS program and text files
• Print Datasets • Launch the SAS System (if installed)
• View multiple file types • Sort by column
• Subset the data • Resize columns and rows
• Perform Text Searches • Launch by right-clicking on Dataset icons
1
From Microsoft Windows 95 Help Topics Menu (Start | Help)

Installing The SAS System Viewer
Since The SAS System Viewer is a free software package, you do not need to purchase a license
to receive the software. OIT has placed a copy of the installation file on the OIT Intranet Home
Page.
To install The SAS System Viewer from the OIT web:
• Start MS Internet Explorer by double-clicking the icon on the Win95 desktop
• In the Address field, type OITWEB and press [ENTER]
• Under the training section, go to the course catalog and click on the NEDAT link
• A page will appear listing the software packages incorporated with NEDAT training. Under
The SAS System Viewer, click the Click Here link and follow the onscreen instructions to
install the software.
Installation
Link
CDER Note: Contact the Help Desk if you experience difficulty in downloading the software
Launching The SAS System Viewer

! If you have not launched The SAS System Viewer by double-clicking on a SAS Transport
file, open the software by going to Start | Programs | The SAS System | The SAS
System Viewer V7
The SAS System Viewer is a Windows based application. The features from the software can be
accessed via the pulldown menu at the top of the screen. Shortcut buttons to common pulldown
menu features are also available on the Toolbar.

Pulldown Toolbar
Menu
Row
Numbers
Main View Column

Window Headings
! If you have not opened define.pdf as of yet, go to File | Open and navigate to the
Z:\N123456\CRT\DATASETS\09 folder
Note: The SAS System Viewer has the ability to open several different dataset types. Consult
the software's Help for a complete listing.
When the lab1.xpt file was clicked, the file opens in the main window. The column headings,
row numbers, and cells appear within the window. Note that the column headers, or variables,
are completely defined. To view the variable name:
! On the pulldown menu, go to View and uncheck the Labels option
The variable names now appear in the column header. Set this Label view to your preference.
Navigating SAS Transport Files

To select a cell, click directly on top on the cell and a box will surround the selected cell. This
box indicates the active cell. You can also use the mouse to scroll up/down or side/side by
clicking or dragging the scroll bars. Use the following tables to navigate the dataset using the
keyboard:
Action Result
← or → keys Move one cell left/right
↑ or ↓ keys Move one cell up/down
[CTRL] + ← or [CTRL] + → Move to beginning/end of row
[CTRL] + ↑ or [CTRL] + ↓ Move to beginning/end of column
[CTRL] + [Home] or [CTRL] + [End] Move to first/last cell in Dataset
[Page Up] or [Page Down] Scroll up/down one screen

Selecting Cells
Before performing any action, you will first need to select the cells involved in the action. As we
have already seen, clicking once on a cell selects that active cell. To select an entire row, click
on the row number to the left of the cells. The selected rows will be highlighted. Click a
Column Header to select an entire column.
Consecutive rows can be selected by clicking on a row number, holding down the mouse button
and dragging up/down. Let go of the mouse to finish selecting rows. Non-consecutive rows can
be selected by clicking on a row number, holding down [CTRL], and clicking on another row
number. Use [SHIFT] in the same manner to select a series of rows.
Selected Row
Non- Series
consecutive
Use the same functions to select consecutive, non-consecutive, or a series of columns. Selecting
all of the rows or columns will select all of the cells in the dataset. You can also click the button
above the row numbers/left of the column headers or go to Edit | Select All on the
pulldown menu to select the entire table.
Sorting Datasets
These datasets can be sorted alphabetically in ascending or descending order. To sort by
column:
! Select the column that will control the sort
! Click the Ascending, , or Descending, , button on the toolbar to sort alphabetically.

The relationship among will remain constant among the other cells in each row.

Sort
Descending
Selected
Column
Sort
Ascending
Sorting Using Query Language

A query is a string expression that utilizes mathematical and Boolean expressions. It is necessary
to have variables setup for the dataset to use query language. To use query language to filter
data:
! Click the Filter button, .
! Enter the following SQL string: Where Age > 50
The Boolean expression is WHERE. The variable is Age, followed by the mathematical formula.
The above example will display all rows that contain a value above 50 in the Age column.

Variable
Query
Results
Currently, to remove the filtering:
! Click the Where button
! Leave the SQL string filed blank
! Click OK
CDER Note: Consult the Help feature on the pulldown menu for additional information on
Query Language, toolbars, and toolbar options in present and future releases of the software.
Searching (Find) Text

Instead of sorting by an entire variable, you may wish to find just one instance of text. To
perform a text search in The SAS System Viewer:
! Click the Find Button,
! Enter the text you wish to find. Look for patient 0290029043
! Click the Find Next Button
The SAS System Viewer will find the next instance for patient 0290029043. To search for the
next instance of the patient ID number, click the Find button again.

While The SAS System Viewer is a user-friendly tool for data analysis, the system may not be
able to handle some large datasets or perform graphing, solver, advanced searches, advanced
queries, or sorting features that are available in Microsoft Excel and Access. StatTransfer will be
used in the next lesson to convert the SAS Transport Files to MS Excel and Access formats.
Before these files can be accessed from StatTransfer, a path must be saved to the shared area
found via the EDR.
Map a Network Drive

Once you have obtained the drive path of the sample NDA, you can access (map) this path on
your desktop. Mapping will create a drive letter on your desktop, which allows easy access to
the NDA shared area from applications used in the review process.
To map to a network drive:
! Minimize any open applications
! Right-click on My Computer and click Map Network Drive
! Select Z as the Drive letter and enter \\cds006\samplenda in the Path: field
! Make sure the Reconnect at logon box is not checked (You may wish to check the
box in order to repeat this process with every logon to your Office PC)
! Click the OK button (you should now be mapped to the Sample shared area)
Once you have mapped to the network drive, a window will open displaying the contents of the
shared area. Double-click on the N123456 folder to reveal the contents of our sample NDA.

Sample NDA
Folder
Sample NDA
Window
As you can see, this window is identical to the EDR. You can now access these files within your
Windows 95 applications. You can also copy specific files or folders related to your discipline
directly to your PC.
Copying Files or Folders to Your Computer

You can copy dataset files directly to your hard drive. This will allow you to convert datasets
without accessing the network. Before you copy a folder or file, you need to make sure you have
available disk space:
! Open My Computer and right-click on the C: drive icon
! Choose Properties on the pulldown menu. Note the free disk space on the C: drive and
click OK.
Free Disk
Space
Used Space
Free Space

To check the size of the file/folder:
! Double-click on the crt folder in the N123456 window
! Double-click on the datasets folder
! Double-click on the 09 folder
! Right-click on the demog.xpt file
! Select Properties from the pulldown menu
File Size
If the size of the file you are copying is less than the space available on your C: drive, continue
to the next step. If the file is larger, you will not be able to copy the file to your C: drive.
! Click OK
CDER Note: It is recommended that you always keep at least 50mb available space on your
hard drive for optimum PC performance.
To copy the file to your C: drive:
! Right-click on the demog.xpt file:
! From the pulldown menu, select Copy
! Move your pointer onto the desktop and right-click. A pulldown menu will appear.
! Highlight and click Paste

File
File
Copy
The file now appears on your desktop!
! To finish this lesson, close My Computer, any shortcut windows, The SAS System
Viewer, Adobe Acrobat , and MS Internet Explorer.
NOTE: These directions for copying files apply to Amendments and Supplements as well.
Make sure when creating a shortcut or copying a folder to note on your desktop whether that
shortcut points to an Amendment, Supplement, or NDA.

Review
This lesson introduced you to accessing NDA, Amendment, and Supplement datasets via the
Electronic Document Room (EDR). The SAS System Viewer was then used to open, navigate,
sort and filter data in SAS Transport files. In order to convert the transport files to other formats,
you learned how to map and save the drive path on your desktop for access by StatTransfer.
The following lesson will cover using StatTransfer to convert the SAS Transport files to file
types compatible with MS Excel, and MS Access. To test your knowledge of the topics covered
in lesson 1, answer the following questions:
• How do you access the Electronic Document Room (EDR)?
• How do you find the location of and NDA or Review using the EDR?
• What is the name of the table of contents file for the crt folder?
• What information is displayed in the column header?
• How do you find additional information on The SAS System Viewer?
• What is a Boolean expression?
• How much available hard drive space is recommended for optimum PC performance?
• What process is used to copy NDA folders?

Lesson 3 - Conversion and
Analysis Tools
In this lesson, you will learn the following:
• About StatTransfer
• How to launch StatTransfer
• Convert SAS Transport Files to MS Excel and MS Access formats
• Use MS Excel and discuss enhanced analysis
• Become familiar with relational data analysis in MS Access
NDA Electronic Data Analysis Training – Lesson 3: Conversion and Analysis Tools 27
About StatTransfer V5
Data created by one program may be needed for analysis within another application. Not only
must the data be transferred, but any supplemental information, such as variable names, missing
values and variable labels must also remain associated with the data in proper format.
StatTransfer is a Windows based tool that allows fast, reliable conversion of data among multiple
formats.
Using a Windows interface, StatTransfer automatically reads data from one program and
transfers the data to the internal format of another supported application. StatTransfer supports
the following formats (NEDAT formats in bold):
• 1-2-3 • ODBC
• Access • OSIRIS
• ASCII – Delimited • Paradox
• DBASE and compatible formats • Quattro Pro
• Epi Info • SAS Datasets
• Excel • SAS Transport Files
• FoxPro • S-Plus
• Gauss • SPSS Data
• JMP • SPSS Portable
• LIMDEP • Stata
• Matlab • Stata Version 6
• Mineset • Statistica
• Minitab • SYSTAT
Consult the HELP button on the Transfer tab in StatTransfer for additional information.
CDER Note: Contact your Focal Point for a licensed StatTransfer installation.
Launching StatTransfer
Electronic NDA datasets arrive in SAS Transport (.xpt) format. The format was chosen based on
the ability to archive and the format’s flexibility. Somest statistical/spreadsheet programs are not
able to open these datasets in their native format. Therefore, StatTransfer must be used to
convert the .xpt files to formats used by some data analysis programs.
28 NDA Electronic Data Analysis Training – Lesson 3: Conversion and Analysis Tools
To Launch StatTransfer:
! On the Win95 taskbar, go to Start | Programs | StatTransfer 5 | StatTransfer
StatTransfer will appear on the Win95 desktop
Dialog Box Input File

Tabs Type
Output File
Transfer Type
Button
StatTransfer Dialog Boxes

The StatTransfer work area consists of five dialog boxes. To access these features, click the tab
at the top of the window. When transferring all of the cases and variables from one format to
another, you can immediately use the Transfer dialog box. The Transfer dialog box is used to
simply choose the input and output file types and locations and will open automatically when
launching StatTransfer.
If you want to select only some of the variables in the input dataset, click on the Variables tab at
the top of the Transfer dialog box. You will be able to select/deselect the variables before
performing the conversion. The Observation tab feature will allow you to select specific
records and cases from your input dataset.
After you have achieved a familiarity with data conversion, you may find the need to change
some of the Options with StatTransfer. The Options dialog box gives you access to changing
the advanced formatting options within the software. Basic Information about the software can
be found in the About dialog box.
Consult the HELP button in the Transfer dialog box for additional information.
MS Excel Conversion
As stated, SAS Transport files are not readily compatible with statistical software used within the
Center. Use StatTransfer to convert these files to formats conducive with Center software.
To convert SAS Transport files:
1. Choose the Input file type and location:
! Use the pulldown arrow in the Input File Type: field to choose the SAS
Transport File option
! Click the Browse button next to the File Specification: field
! Navigate to the folder path, Z:\N123456\CRT\DATASET\09\ that was created in the

second lesson
! From the File Name: field, select lab1.xpt
! Click OK
When the input file has been selected, a message, the Variable Selection Indicator, will appear
displaying that all of the variables in the dataset have been selected.
2. Select the Output file type and location
! In the Output File Type: field, use the pulldown arrow to select the first format
discussed, Excel
! Click the Browse button next to the File Specification: field and navigate to the
folder C:\CLASSES\NEDAT\DATASETS
! Rename the file lab1.xls
! Click OK in the Save As window
SAS XPT
Input
Excel Output
Transfer
Button
! Click the Transfer button. (If you need to stop the conversion, the Transfer button is
now labeled Stop. Press the button if you wish to halt the transfer)
! Once the conversion is complete, click the OK button to complete the transfer. The total
number of transferred cases will appear at the bottom of the Transfer dialog box.
MS Excel can now be used to analyze the newly created SAS Dataset.
About Microsoft Excel

Microsoft Excel is the Windows based spreadsheet program of Microsoft Office. Excel uses
formula creation, as well as natural language formulas that let you build equations using your
own terminology. Charting options in Excel allow you to present data in chart types such as pie-
of-pie and bubble charts. Since Excel is part of the Microsoft Office suite, you have the ability
in Excel to build hyperlinks and import/export information to/from other Microsoft Office
documents.
Open MS Excel Worksheet

To open Microsoft Excel:
! On the Win95 taskbar, go to Start | Programs | Microsoft Excel
The MS Excel window is similar to The SAS System Viewer window. There is a pulldown
menu at the top of the screen, with several toolbar options available.
To open the newly created Electronic Submission worksheet:
! On the pulldown menu, go to File | Open
! Navigate to the C:\CLASSES\NEDAT\DATASET folder
! Open the LAB1.XLS file
Pulldown Toolbars
Menu
Formula Bar Column

Letters
Row Variables
Numbers
Several noticeable differences exist between the MS Excel and The SAS System Viewer
windows. The Variables that were the Column Headers in The SAS System Viewer have been
converted to cells. Also, there is a Formula bar that allows new data entry and formula
calculations.
MS Excel Features
While The SAS System Viewer allows for basic sorting and text searches, Microsoft Excel has
the capabilities to perform the following advanced features (NEDAT in bold):
• Advanced Sorting • Graphing
• Auditing • Links to other MS Office Applications
• Formula Calculations • Editing and revision tools
• Conversion to other formats • AutoFilter
In order to sample the one of the power analytical tools in MS Excel, perform a quick graphing
of the newly converted data.
Using the Excel graphing features, compare the lab values at baseline and after drug for the first
patient, 0290019584:
! In the LADCODE column, click in the first cell of row 2.
! Hold down the mouse and drag down to the last LABCODE value for the patient (row 13 -
SERUM SODIUM)
Selected
Values
! Hold down [CTRL] and select all the lab values (LVALUE column) for the patient
! On the standard toolbar, click on the Chart Wizard,
! Since the values were selected, click the Next button three consecutive times until you get to
the last Chart Wizard window
! Since some of the text in the LABCODE column is large, check the As new sheet button to
create a new worksheet with the table
! Click Finish
A new worksheet has been created that shows the baseline value of the lab next to the value after
treatment. As the chart illustrates, there was a slight increase in chloride and a slight decrease in
sodium.
This exercise is a basic example of the charting tools available in MS Excel. Consult the Help
option on the pulldown menu for specific information about these analytical, and additional,
features available in MS Excel.
CDER note: OIT offers an Introduction to Microsoft Excel course. Consult the OIT Home
page (HTTP://OITWEB/OIT) for dates and registration.
While MS Excel offers these advanced analytical features, you may have a need to perform
advanced relational queries and reports. MS Office also have a relational database application,
MS Access, that is compatible with SAS Transport files and Stat Transfer.
You can close MS Excel at this point in the training.
Microsoft Access Conversion

In order to convert the network copies of the SAS Transport file to MS Access, we need to go
back to the Stat Transfer software.
To convert the dataset to MS Access:
! On the Win95 taskbar, click on the Stat Transfer button
! Click the Reset Button at the bottom of the Stat Transfer window
! Repeat Step 1 under the MS Excel Conversion section of this lesson
! Make sure to choose Access 95-97 in the Output File Type field
! In the Save As window, navigate to C:\CLASSES\NEDAT\DATASETS and click on the

filename lab1.mdb (A sample database was created. StatTransfer will add the converted
table to the database)
! Click the Transfer button
XPT Input MS Access

Output
! Click the Reset button
! Repeat the previous conversion steps, this time converting the file
Z:\N123456\CRT\DATASETS\09\DEMOG.xpt
After converting the second table, click the Exit button on StatTransfer.
About Microsoft Access

Microsoft Access is a relational database management application that integrates and organizes
information from spreadsheets and other databases. Multiple datasets from an Electronic NDA
can be converted to multiple MS Access tables, where advanced query functions can be utilized.
To open MS Access:
! On the Win95 taskbar, go to Start | Programs | Microsoft Access.
! When Access is launched, a window appears with several options:
! Make sure the Open an Existing Database radio button is checked and choose the
More Files… option
! Open the C:\CLASSES\NEDAT\DATASET\LAB1.MDB file
The datasets we converted are now displayed as icons in the Tables tab of MS Access. To
open a table, double-click the lab1_jmp icon on the Tables tab.
Pulldown
Menu
Variables
Toolbar
As you can see, MS Access maintains the variables as column headings. The Access table is
similar to the Excel Spreadsheet and the two applications share many of the same toolbar
functions.
MS Access Features
When you close the Access table, you will be taken back to the main Access window. From
here, you can access the features of MS Access by clicking on the related tab. Click on the
Queries tab in the MS Access window.
Tab Options
Tables
Similar to the data we have been viewing in The SAS System Viewer and MS Excel, the table
feature is used to provide the data used in the additional MS Access Features.
Queries
Like to SQL string in The SAS System Viewer, queries are used to view, change, and analyze
data in various formats. You can also use them as the source of data for Forms and Reports.
Forms
A form is a customized, visual interface that allows you to access/add to your data in a variety of
ways.
Reports
A report is an effective way to customize the appearance of your data in a your desired output
format (e.g., printed.) Because you have control over the layout of a report, you can tailor the
information specific to your discipline.
In order to sample one of the powerful relational tools available within MS Access; let's take a
look at a sample Query that was previously created, lab1.mdb.
Use the query functions of Access to find any lab values above 140. Display the patient's age,
sex, race and patient ID number:
! Click on the Lab value vs race query that has been created
! Click on the Open button in the Query window.
DEMOG_JM Lab1_JMP
variables variable
The query was set up to first sort the DEMOG_JM table by the PTID, AGE, SEX, and RACE
variables. However, the LVALUE was listed in the LAB1_JMP table. Because the variable
PTID was constant in both tables, the query was able to join the two tables at that variable and
query the last field from the LAB1_JMP table in order to display all LVALUES that are above
144.
Consult the Help feature on the pulldown menu to learn more about Macros, Modules as well as
all additional features of MS Access.
CDER note: OIT offers several introductory and advanced tables and reports classes in MS
Access. See the OIT Home page (HTTP://OITWEB/OIT) for dates and registration
information.
! Close MS Access and StatTransfer to complete this lesson.
Review
In the previous lesson, we learned how to perform sorting and query functions on datasets using
The SAS System Viewer. This lesson explored how to convert SAS Transport files using
StatTransfer to MS Excel and Access to perform advanced analysis and queries. The next lesson
will cover using an advanced, but user friendly software package, JMP, to consolidate all of the
functions discussed in the three applications covered in the previous two sections.
To test your knowledge of the concepts and techniques you learned in this lesson, answer the
following questions:
• Why do you need StatTransfer to convert NDAs data files?
• In the Open window of StatTransfer, what field do I need to change to open a SAS
Transport file?
• What is a Variable?
• How do I find additional information on MS Excel and Access?
• Can I open the SAS Transport files located on the network to perform my analysis?
• Is there additional training offered by OIT for Excel and Access?
Lesson 4 – JMP Features
In this lesson, you’ll learn how to do the following:
• Launch JMP
• Import network SAS Transport files into JMP
• Navigate and Select data
• Access the Data Definition Table (define.pdf)
• Save a JMP file
NDA Electronic Data Analysis Training – Lesson 4: JMP Features 41

About JMP
JMP is a statistical software package developed by the SAS Institute. It provides a graphical
interface to display and analyze data. JMP includes:
• a spreadsheet for viewing, editing, entering, and manipulating data
• a broad range of graphical and statistical methods for data analysis
• options to highlight and display subsets of the data
• tools to sort and combine tables
• a calculator for each table column to compute values
• a facility for grouping data and performing subgroup analyses
• tools for moving analysis results between applications and for printing
This lesson is an introduction to JMP. Basic JMP navigation, cell selection, and column and row
manipulations is covered. The next lesson will demonstrate how JMP can be used to review data
in much the same way one would use a paper or PDF Case Report Tabulation. In addition,
powerful data manipulation and analysis tools available in JMP will be examined.
CDER note: Contact your Focal Point for JMP license and installation.
Launch JMP
When JMP is installed on your PC, a shortcut to the software can be found in the Programs
section of the Start menu.
To launch JMP:
! On the Win95 taskbar, go to Start | Programs | JMP | JMP
You may also wish to side step this procedure in the future by creating a desktop shortcut to
JMP.
To create a desktop shortcut:
! Minimize any open windows
! Right-click on the Win95 desktop
! From the popup menu, choose New | Shortcut
42 NDA Electronic Data Analysis Training – Lesson 4: JMP Features

! When asked for the command line, enter C:\JMP\Jmp.exe (use the browse button if you are
not sure of the JMP file location)
! Change the name of the shortcut to JMP
! Click the Finish button
! To access JMP in the future, double-click the desktop shortcut.
Either one of these option swill launch JMP and take you to the main JMP screen.
Pulldown Toolbar
Menu
Rows Columns
Import a SAS Transport File

In the previous lesson, we used StatTransfer to convert .xpt files to MS Excel Worksheets and
Access tables. JMP has the capability built-in to do this conversion from SAS Transport files.
To import a SAS Transport file:
! On the pulldown menu, go to File | Import | SAS Transport file…

! Navigate to Z:\N123456\CRT\DATASETS\09
! Because the .xpt file extension is new, some software versions may not immediately
recognize the file extension. Change the Files of type: field in the bottom left hand corner of
the import window to All Files (*.*)
! Click on the lab1.xpt icon
! Click Open
The SAS Transport file is now in JMP format.
Cursor
Forms
Scroll Bars

Navigating a JMP Dataset
Cells are the location where rows and columns intersect. To select a cell, click directly on top on
the cell and the cell will be highlighted. This highlighting indicates the active cell. You can also
use the mouse to scroll up/down or side/side by clicking or clicking and dragging the scroll bars.
Use the following tools to navigate the dataset using the keyboard:
Action Result
← or → keys Move one cell left/right
↑ or ↓ keys Move one cell up/down
[CTRL] + ← or [CTRL] + → Move to beginning/end of visible row
[CTRL] + ↑ or [CTRL] + ↓ Move to beginning/end of visible column
[Home] or [End] Move to first/last cell in dataset
[Page Up] or [Page Down] Scroll up/down one screen
Cursor Forms
Cursor forms are present and can be selected to do the following functions:
arrow - the default cursor form, present when you hover over the deselect areas in the
upper left hand corner or when hovering over the data modeling type box in the column header
cross - when over a column header or a data cell, the cross indicates the ability to select text.
When you click on the cross cursor, the text highlights and can be edited. The cursor then
becomes an I-beam.
I-beam - this is a vertical blinking bar which allows you to edit text in a column header or
data cell
open cross - is present when you move into a column or row selection area. Use the open
cross to select a single row or column. Double-click, using the open cross in the column header
to get additional column information.
Selecting Cells
Before performing any action, you will first need to select the cells involved in the action. As we
have already seen, clicking once on a cell selects that active cell. To select an entire row, click
on the row number. The row number will be highlighted. Click a Column Header to select an
entire column.
Consecutive rows can be selected by clicking on a row number, holding down the mouse button
and dragging up/down. Let go of the mouse to finish selecting rows. Non-consecutive rows can

be selected by clicking on a row number, holding down [CTRL], and clicking on another row
number. Use [SHIFT] in the same manner to select a series of rows.
Deselect
Area
Non-
consecutive
Use the same functions to select consecutive, non-consecutive, and a series of columns.
Selecting all of the rows or columns will select all of the cells in the Dataset. You can also click
the button above the row numbers/left of the column headers or go to Edit | Select All on
the pulldown menu to select the entire table.
Deselecting Cells
To deselect columns, click in the Columns detail area in the top left corner of the dataset. To
deselect rows, click in the Rows detail area in the top left corner of the dataset.
Move and Hide Columns

To move a column:
! Select the column Study
! On the pulldown menu, go to Cols | Move Columns
! Select the After radio button
! Highlight PTID

! Click the Move button
You may also choose a different Move option from the Cols pulldown menu. Repeat the steps to
move the column back
To hide a column:
! Select the PTID and PATFDA columns
! On the pulldown menu, go to Cols | Hide Columns
Those columns now disappear from the table. To view the columns again:
! On the pulldown menu, go to Cols | Unhide Columns
! Select the columns to unhide
! Click the Add button
! Click OK

Column Headers
The Column Headers contain the column's variable name, type, field width, format, modeling
type, level, data validation information, and general text notes about the column. If the column is
computed, its formula is displayed in the box in the lower left corner of the dialog. The Notes:
field will automatically include the variable label (see Lesson 2.) A note field can also hold up
to 29K characters.
To access a column header:
! Double-click on the PTID column header using the open cross
Column
Name
Data Source
Data Type
Notes
Modeling
Type
Column Header Fields:
Field Content
Col Name Contains the column name
Validation set up a table of acceptable values
Data Type Choose numeric or character
Modeling Type Choose Continuous (numbers), Ordinal
(characters or numbers that have an order), or
Nominal (characters or numbers with discrete
values)
Data Source Choose Formula or No Formula
Notes Variable label
! Click on the OK button to remove the column header.

Saving a JMP File
Since the network datasets cannot de edited, you must save any of your work as a JMP file. If
you do not save your changes, all work will be lost and you will have to import the SAS
Transport file again.
To Save:
! On the pulldown menu, choose File | Save As
! Navigate to the C:\CLASSES\NEDAT\DATASET folder
! Rename the file DEMOG.JMP
! Click the Save button

Review
In this lesson, you learned the basic features of JMP. The next lesson will discuss the tools
needed to perform statistical analysis and export your information to other applications.
• How do you import a SAS Transport file?
• Where do you click to deselect Columns? Rows?
• What is the file name of the Data Definition table?
• Where else can you find a variable definition in JMP?
• How do you navigate to the end of a JMP dataset?
• Can JMP view the SAS Transport NDA data files located on the network?
• Does importing a SAS Transport files automatically save a JMP file?

Lesson 5 – JMP Tools
In this lesson, you’ll learn how to use JMP analytical tools. Each tool will contain a brief
explanation, as well as exercises in bold that apply the topic to NDA data analysis. The
following tools are covered in this lesson:
• The Sort Command
• Select Rows "Where…"
• Subset Command
• Search Command
• Group Summary
• Distribution of Y
• Exclude/Include
• Adding a Computed Column
• Fit Y by X
• Exporting to MS Excel and Word
NDA Electronic Data Analysis Training – Lesson 5: JMP Tools 53

Sort Command
The Sort command sorts a dataset by columns. Use the sort dialog box to add/remove columns
as sort fields.
Exercise 1: Use the sort command to sort the table by age and sex, in ascending order.
To sort the table:
! On the pulldown menu, select Tables | Sort
! Select AGE as the first sorting variable
! Click Add
! Select SEX as the second sorting variable
! Click the Add button
! Click the Sort button
Variables
Ascending/D
escending
Sort By:
variables
You can also sort in ascending/descending sort by clicking on . Add the variables
in order, as procedures in the lesson are order sensitive!
! Close the new file, Untitled2.jmp, to move on to the next topic.
Select Rows "Where…"

When you are only interested in selecting a group of records (rows) that meet a specific criterion,
you can use JMP tools to choose these specific rows.
Exercise 2: Display only the data for serum sodium.
! On the pulldown menu, go to Rows | Select | Where…
54 NDA Electronic Data Analysis Training – Lesson 5: JMP Tools

! In the Column area, Click on LABCODE
! Make sure the equation is Equals
! In the free form character field, type SERUM SODIUM
! Click OK
Variables Free form

Characters
The rows meeting this criterion are highlighted in black.
Subset
Use the Subset command if you wish to pull selected records into a separate, but linked table.
Exercise 3: Subset the selected serum sodium rows of data.
! On the pulldown menu, go to Tables | Subset
Subset
Variable
Only those highlighted serum sodium rows and columns appear in the new table.

! Close the newly created Untitled2.jmp file and deselect the highlighted serum sodium to
move to the next topic.
Search Command
The Search command is used to find and replace text. This command allows you to search for a
series of words in a character column, or locate strings with unwanted leading or trailing blanks.
Exercise 4: Search for the patient with ID number, 0000000.
! On the pulldown menu, go to Edit | Search | Find
! In the Find what: field, type 0000000
! Click the Find button
Find what:
field
Replace
features
Find features
The first instance of the text, 0000000, is highlighted in the table. To search again, repeat this
process. The Find what: field will automatically contain the previous entered text.
Find Features:
Match Case: gives you a case sensitive search
Match whole words only: locates words with at least one leading and one trailing blank
Search by row and Search by column: determine whether the search is performed along rows
or columns.
! Deselect all rows and columns to continue.

Group Summary
The Group/Summary command creates a new JMP table that summarizes columns from the
active data table. The summary table has a row for each row or combination of levels of all
grouping variables. Up to this point, many reviewers relied on sponsors to do the tasks made
available with the Group/Summary command.
Exercise 5: Use the Group/Summary command to find the number of tests per lab test
category.
! On the pulldown menu, go to Tables | Group Summary
! In the Columns field, select LABCODE
! Click the Group button
! Click OK
Stats
functions
Variables
Subgroup
The new table shows the lab test categories, as well as the number of rows (tests) for each
category.
! Close this new table before moving on to the next example.
You can also group by more than one variable, sub group, and add columns of descriptive
statistics to the summary table for any numeric column in the source table. When selecting
multiple variables, make sure to add them in the same order you wish the variables to appear in
the table.
Exercise 6: Use Group/Summary to find the mean lab value for each test, grouped by
treatment assignment, and subgrouped by study period (baseline vs. treatment).
! In the Columns field, select TRT

! Select LVALUE
! Click on the Stats button and choose Mean
! Select PHASE
! Click on the Subgroup button
! Click OK
The new summary table lists the mean lab values by treatment group, and is subgrouped by study
period. Take note that in the last few rows, the table displays how the drug affects the serum
sodium Values! Save this table, as it will be used later in this lesson:
! On the pulldown menu, go to File | Save As
! Save the file as C:\CLASSES\NEDAT\DATASET\LABMEANS.JMP
! Leave the table open and display the original table by going to Window | LAB1_JMP.
Distribution of Y
The Distribution of Y function is used to provide a partitioning of values with histograms, as
well as other graphic and text reports.
Exercise 7: Use the Distribution of Y function to find the distribution of post-treatment

serum sodium values in this study.
1. Group by the table by LABCODE
! Click OK
2. Highlight the serum sodium row in the newly created summary table
Selected Row

3. Select the original table and subset the data to get a table for just serum sodium values.
! Go to Window | LAB1_JMP
4. Assign LVALUE as "Y"
! Click on the right square above the variable name LVALUE in the column header
! Choose Y from the pop up menu
LVALUE
column
5. On the pulldown menu, select Analyze | Distribution of Y (you can also click
on the toolbar)
The histogram, box plot, quintiles, and statistical moments are displayed. The display can be
altered by clicking on the “check” mark that brings up a menu in the lower left of the window.
The graph may not provide the necessary information because the tables used combines baseline
and post treatment values. You will want to exclude all baseline values before performing a
Distribution of Y.
! Return to our serum sodium table (Untitled2) to complete the next task.
Exclude/Include
The Exclude/Include feature allows you to exclude certain rows from statistical analysis.
Exercise 7 (cont.): Reproduce the previous graph without baseline values.
1. Select the baseline value rows from this table

! On the pulldown menu, go to Rows | Select | Where…
! In the Column Area, choose PHASE
! Make sure equals is the equation
! In the free form character area, type 0
! Click OK
All of the rows where PHASE equals 0 are now selected.
2. Exclude the selected baseline rows
! On the pulldown menu, go to Rows | Exclude/Include
LVALUE
rows
The excluded rows are marked with . Data will remain excluded until Exclude/Include
is chosen again.
3. Distribute by Y
! On the toolbar, click
! Cascade windows to show both charts

With Baseline Without Baseline
The chart now excludes the baseline values from the analysis.
Adding a Computed Column

The JMP calculator can be used to create derived variables by adding computed columns.
Exercise 8: Use the JMP Calculator to find the change from baseline for each lab value.
! On the pulldown menu, go to Window | LAB1_JMP
! On the pulldown menu, go to Cols | New Column
! In the Col. Name field, type CHANGE
! In the Data Source: field select Formula from the drop down selection box

! Click OK. This brings up the calculator window
Column
Selector List
Formula
Display Area
Keypad
! Select LVALUE from the Column Selector List
! Click the minus button, , in the Keypad
! Select LABB from the Column Selector List
! Close the Change window
The CHANGE column now displays the change from baseline for each lab value.
Fit Y by X
This function allows the use of statistical tests such as chi-square, T-tests, and ANOVA.
Exercise 9: Use the Fit by X feature of JMP to find if there is a statistically significant
difference in post-treatment serum sodium values across treatment groups.
1. Group the table by LABCODE and PHASE
! Make sure that the data modeling type for TRT is Ordinal and LVALUE is Continuous
Modeling
Types

! In the Columns field, select PHASE
! Click OK
2. Subset the data
! Highlight the row where LABCODE is equal to Serum Sodium and PHASE is 1 (this is a
second way to select out post-treatment serum sodium values, The first way was covered in
the distribution of Y - Include/Exclude)
! Go to Window | LAB1_JMP
A new table is created that contains all the rows where LABCODE is equal to Serum Sodium and
PHASE is 1
3. Fit Y by X
! On the pulldown menu, go to Analyze | Fit Y by X (or press )

Column X/Y Buttons
Select
Since we have not yet designated our X and Y axis, a JMP window appears asking for the X and
Y columns. We need to designate TRT as X and the LVALUE variable as Y:
! Select TRT in the Column Select Area
! Click X button
! Select LVALUE in the Column Select Area
! Click the Y button
! Click OK
Analysis P value
Options

JMP creates a scatter plot of serum sodium values according to treatment. Click on the
Analysis arrow and select Means/ANOVA/T-test. JMP automatically selects ANOVA as
the appropriate statistical test for an ordinal x variable with more than 2 values, and a continuous
Y variable. Under Analysis of Variance, the p value is shown in the lower right under
“Prob>F” (p<0.0001).
The conclusion is that there is a statistically significant difference in serum sodium values among
the 3 treatment groups.
Exporting to Excel and Word

Now that you have completed your statistical analysis, you may want to export the information to
applications for writing reports or additional analysis. Data, as well as charts and graphics can
be exported to the spreadsheet, MS Excel, or word processing, MS Word, applications used in
the Center.
Let’s go back to the table, labmeans.jmp, saved for serum sodium values.
Exercise 10: Copy the labmeans data to an MS Excel spreadsheet:
! On the pulldown windows, go to Window | labmeans
! Place your cursor over the first cell in the table. Make sure open cross, , is displayed
(click deselect columns/rows if necessary.)
! Click, hold down on the mouse, and drag down to the right over all cells so the selection box
covers all of the cells. All of the column and rows are highlighted.
Selection
Selected Box
Row/Columns
! On the pulldown menu, go to Edit | Copy
! On the Windows 95 taskbar, click Start | Programs | Microsoft Excel
! On the Standard Excel toolbar, click the paste button,

Note: Column labels (variables) are not copied
You can now use Excel to enhance the look of the data, or perform additional analysis or
graphing. In order to move to the next Topic, close Excel and do not save any changes.
In additional to pasting the cells of a dataset into Excel, graphics and data can also be exported
into MS Word.
Exercise 11: Copy the scatter plots (Fit y by X) paste the chart into Word.
! On the pulldown menu, go to Window | Untitled 3: Y by X
! From the toolbar, choose the Scissors tool,
! Place the cursor at the open end of the scissors on any corner on the chart
! Click and hold down on the mouse
! Drag a box over the entire chart
Selection
Box
! On the pulldown menu, go to Edit | Copy
! On the Windows 95 taskbar, go to Start | Programs | Microsoft Word
! On the Standard Word toolbar, click the paste button,
You may wish the chart just pasted into Word to not float over the text. In order to perform this
function, you can use the Paste Special feature in Word:
! On the Standard Word toolbar, click the undo button,
! On the pulldown menu, go to Edit | Paste Special
! Choose Picture from the As: field and uncheck the Float over text box. This will prevent the
picture from floating over the text on the page (you may also use additional Word picture
formatting procedures.)

As: field Float
over text
Although the image looks the same, it will be placed within the text and features such as
justification, tables, etc. can be used to align the graphic.
In addition to the chart, there are several tables located on the JMP window. These tables can be
copied and pasted as graphics in the same manner as the chart. However, since JMP recognizes
the text in these tables, the data can also be copied as text.
Exercise 12: Copy and paste the Analysis of Variance table from JMP to Word.
! Press [ENTER] to move down from the pasted chart in Word
! On the Windows 95 taskbar, click the JMP button,
! Make sure the Scissors tool is selected. Click and drag a box over the Analysis of Variance
table
! On the pulldown menu, go to Edit | Copy as Text
! On the Windows 95 taskbar, click the Word button
! On the Standard Word toolbar, click the paste button,
The text has been pasted into word with tab delimitation separating the columns.
You can use Word formatting and table skills to convert the text, as long as the tab separations
are proportionate, to a table.
You are now ready to write your report and finish for the day!

Review
In this lesson, you learned the user-friendly analytical tools available in JMP. It may require
practice and review of the exercises in this lesson until you are comfortable with JMP analytical
tools. Access to the files is available for all Center staff.
The next lesson will discuss additional Support for NDA Electronic Data Analysis, from manuals
to OIT support.
• What can be arranged using the Sort Command?
• What are the three data modeling types?
• Where on the pulldown menu do you find the Distribution of Y and Fit Y by X
commands?
• What type of data source in the New Columns window will launch the JMP Calculator?
• What tool is used to rule out the baseline from statistical analysis?
• What tool is used to copy graphics as text?

Lesson 6 – Support
Now you are ready to go and work on Electronic Data. But what happens when you have a
question or forget something covered in class? Is there advanced training? When should the
Help Desk be called and what sort of information do you need to provide them to help find
answer?
It is likely that a person who can find an answer to their question on their own will not have
that same question again. This lesson covers how to find answers when to access additional
technical and peer support.
This short lesson will instruct you how to access the following types of support in the Center:
• Classes and Manuals
• Additional Training
• Help Menu
• OIT Support
• Peer Support
NDA Electronic Data Analysis Training – Lesson 6: Support 71

Classes and Documentation
Class and Course Evaluation
The NDA Electronic Data Analysis Training (NEDAT) class offered by OIT is dependent upon
you to make constructive insights and comments on the course. Please make sure to fill out and
return the OIT Course Evaluations at the end of class. These evaluations will help us shape the
class so it is most beneficial to review staff.
Manual and ERSR Guidance
The NEDAT manual can be found on the OIT Web (HTTP://OITWEB/OIT) under the
Documentation/ Applications Training section. Those attending the NEDAT
training have also been asked to bring a formatted, 3 ½” floppy disk to class. PDF copies of the
NEDAT manual and ERSR guidance can be copied to a floppy disk.
To copy the NEDAT manual and guidance in PDF:
! Minimize any open windows
! Insert the 3 ½ “ floppy into the floppy drive
! Double-click on My Computer
! Double-click on the Sample on ‘cdnta2’ (Z:) drive
! Double-click on the PDFs folder
! Hold [CTRL] down and click on both the nedat.pdf and the 2353dft.pdf files. Both files
should be highlighted.
! Right-click over the highlighted files
! From the pulldown menu, choose Send to | 3 ½ Floppy (A)
! Once the files are done being copied, remove the floppy disk
72 NDA Electronic Data Analysis Training – Lesson 6: Support

Trifolds
Quick reference desktop trifolds for JMP and NEDAT have been provided in class. Use these
trifolds for answers to frequently asked questions. Additional trifolds for other OIT courses can
be found via the OIT Help Desk.
Additional Training
The following Advanced NEDAT Software courses are currently available, or are being
formulated, within the Center.
MS Windows 95 and Internet Explorer
OIT offers introductory courses or tutorials for each. Consult the OIT web
(HTTP://OITWEB/OIT) under the Training Schedules area for documentation and class
schedules.
MS Word
OIT Offers Introductory, Formatting, and MS Word Tables Classes. Consult the OIT Web site
for details.
Adobe Acrobat
OIT offers introductory courses, as well as NEST, which incorporates the use of Acrobat in the
Electronic Review process. Consult the OIT Web site for details.
JMP
Medical Officers are currently offering advanced NEDAT courses in JMP per discipline.
Contact Randy Levin (LEVINR), Associate Director for Electronic Review, ORM for details on
attending, or instructing advanced JMP courses.
NDA Electronic Submissions Training (NEST)
NEST covers how to search for a specific Electronic NDA. Adobe Acrobat is then used to open,
navigate, view, follow links, create electronic notes, and copy and paste text and graphics into
MS Word. Consult the OIT Web site for details.
MS Excel and Access
OIT offers introductory courses on Excel and Access, as well as advanced query and report
writing courses for Access. OIT and ERSR management are currently formulating advanced
NEDAT courses for both software packages. Contact Randy Levin (LEVINR), Associate
Director for Electronic Review, ORM is you are interesting in attending, or assisting in the
creation of NEDAT Excel ands Access courses.
NDA Electronic Data Analysis Training – Lesson 6: Support 73

Help Menus
Access the help menus in each of the applications discussed under Help on the pulldown menu
for each application respectively.
OIT Support
If you are unable to find the answers you need via class instruction, manuals, or the Online
Guides, please call the Help Desk at X7-0911 or e-mail them at HELPDESK. Please indicate
whether your problem is related to an application or Electronic Submissions feature. Questions
related to MS Windows, MSIE, Adobe Acrobat, The SAS System Viewer, StatTransfer, MS
Excel, MS Access, JMP, and MS Word can be answered by the Help Desk or visited by OIT
Desktop Support. Questions related to Electronic Submissions (missing folders, files, etc.) are
forwarded directly to OIT Level II Support.
Peer Support
Some of the best resources for learning are those who work with us every day. Those of you who
have taken the NEDAT course and have a firm grasp of the Electronic Data Analysis process can
help share your expertise with others by acting as a mentor to those seeking information and
feedback to their ERSR related situations. Also, if you have an interest in contributing to the
additional Excel, Access, and JMP NEDAT courses, contact Randy Levin (LEVINR), Associate
Director for Electronic Review, ORM.
Look for a more formalized Peer Support system as more Center staff become familiar with
NEDAT and ERSR regulations.
Thank you for your participation and please take advantage of all support options available in the
Center.
74 NDA Electronic Data Analysis Training – Lesson 6: Support

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 corre
sponding 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.
Rockville, Maryland 20857
Presents…
NDA Electronic Submissions Training

NEST
Contents
INTRODUCTION ..........................................................................................................................I
Prerequisites.................................................................................................................................. i
Conventions .................................................................................................................................. i
CHAPTER 1 – NEST PRESENTATION.................................................................................... 1
CHAPTER 2 - ACCESSING ELECTRONIC SUBMISSIONS ................................................ 7

Electronic Document Room (EDR) ............................................................................................. 8
Map a Network Drive ................................................................................................................ 10
Create a Desktop Shortcut ......................................................................................................... 10
Copying Folders to Your Desktop ............................................................................................. 11
Review ....................................................................................................................................... 15
CHAPTER 3 - EXPLORING ELECTRONIC SUBMISSIONS ............................................ 17

Opening the Electronic Submission Table of Contents ............................................................. 18
Looking At the Work Area ........................................................................................................ 18
Looking At the Status Bar.......................................................................................................... 19
Following A Link....................................................................................................................... 19
Compare Word........................................................................................................................... 19
Using the Browse Buttons.......................................................................................................... 20
Retracing Your Viewing Path .................................................................................................... 21
Changing the View Magnification............................................................................................. 21
Using Bookmarks....................................................................................................................... 22
Searching For A Word - the Find Tool ...................................................................................... 23
Searching For Words and Phrases in the Indexes...................................................................... 24
Review ....................................................................................................................................... 31
CHAPTER 4 – ELECTRONIC REVIEW TOOLS.................................................................. 33
Annotations ................................................................................................................................ 34
Graphic Markup Tools ............................................................................................................... 35
Delete, Change Preferences For, Or Change Individual Properties For Notes And Markup
Annotations: ............................................................................................................................... 37
Summarize Annotations ............................................................................................................. 38
Copy and Paste Text .................................................................................................................. 39
Copy and Paste Tables ............................................................................................................... 40
Copy and Paste Graphics ........................................................................................................... 42
Review ....................................................................................................................................... 45
CHAPTER 5 – SUPPORT .......................................................................................................... 47

Classes and Documentation ....................................................................................................... 48
Adobe Acrobat Online Guide .................................................................................................... 48
Acrobat Preferences ................................................................................................................... 49
OIT Support ............................................................................................................................... 49
Peer Support............................................................................................................................... 49
APPENDIX - EXERCISE SOLUTIONS................................................................................... 51

Introduction
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.
NDA Electronic Submissions Training (NEST) covers how to search for a specific NDA via the
Electronic Document Room (EDR) Intranet site as well as map the drive path of the folder using
Windows 95 (mapping). Adobe Acrobat is then used to open, navigate, view, follow links, create
electronic annotations, mark text, and copy and paste text, tables, and graphics into other
applications from a sample electronic NDA.
The NEST program does not end with in-class instruction. The final chapter includes support
options for reviewers who have taken the NEST class, but require access to additional technical
support. NEST incorporates the use of an extensive classroom manual, desktop reference guides,
and the online guides for on-hand desktop support and also instructs reviewers how to access
support via OIT and peers within the Center.
Prerequisites
Before beginning these chapters you should have a working knowledge of Windows 95 and its
conventions. In particular, you should know how to do the following:
• Use a mouse and standard Windows or Macintosh menus and commands.
• Open, save, and close files.
• Resize and position application and document windows on the screen.
For help with any of these techniques, please see your Windows 95 documentation or the CDER
OIT Help Desk. Classes in Windows 95 are offered by OIT.
Conventions
Variables and commands are in the courier new font. Each topic includes an exercise in
bold. Answers to the exercises can be found in the Appendix at the end of the manual.
NDA Electronic Submission Training – Introduction i

Chapter 1 – NEST
Presentation
Please use the blank lines to take notes during the presentation.
This chapter will take approximately 15 minutes to complete.
NDA Electronic Submission Training – Chapter 1: NEST Presentation 1

Slide 1 _______________________________
NDA Electronic Submissions
Training (NEST) _______________________________
_______________________________
CDER/OIT Training
_______________________________
Please Sign-In Before Seating
and Make Sure to Logon with _______________________________
Your Username
_______________________________
_______________________________
____________________________
Slide 2 _______________________________
NEST Overview
_______________________________
❚ Review of “Providing Regulatory
Submissions in Electronic Format - NDAs” _______________________________
❚ Review of Portable Document Format (PDF) _______________________________
❚ Blueprint of Guidance _______________________________
❚ NEST Objectives
_______________________________
_______________________________
____________________________
Slide 3 _______________________________
CDER’s ERSR Goals for 2002
_______________________________
❚ All submissions can be received and
archived electronically _______________________________
❚ All electronic submissions, reviews, and
other related information can be accessed _______________________________
by the reviewer through a desktop
computer _______________________________
❚ Data analysis
❚ Publicly available information is on the
Internet
_______________________________
_______________________________
____________________________

Slide 4 _______________________________
Incoming Electronic NDAs
_______________________________
Submitted to
Central Document Room _______________________________
_______________________________
Placed on CDER Network
_______________________________
Accessed by Reviewers
_______________________________
_______________________________
____________________________
Slide 5 Portable Document Format _______________________________

(PDF)
_______________________________
❚ Flexible format - displays and preserves
fonts, layouts and graphics
_______________________________
❚ Archivable
❚ CDER Document Repository (DFS)
_______________________________
❚ ICH, de facto industry standard
❚ Free viewer (Reader)
_______________________________
❚ User-friendly navigation
❚ Multiple sources (HTML, MS Word, etc..)
_______________________________
❚ Strong commitment from Adobe
_______________________________
____________________________
Slide 6 Each NDA main folder _______________________________

contains
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
____________________________

Slide 7 Each NDA Section folder _______________________________
contains
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
____________________________
Slide 8 Each NDA PDF files Contains: _______________________________

_______________________________
❚ Links: ❚ Document Information
❙ TOCs link to Title Field _______________________________
corresponding ❙ contains pertinent
PDFs information to each _______________________________
❙ Bookmarks file (patient ID#,
created as TOCs Site #, Study #,
etc.)
_______________________________
❙ cataloged for
searching _______________________________
_______________________________
____________________________
Slide 9 _______________________________
NEST Objectives
_______________________________
❚ NDAs exist on network
❚ NDAs accessed via Electronic Document _______________________________
Room (EDR)
❚ Map to NDA network area _______________________________
❚ Learn how to copy NDAs to hard drive
❚ Adobe Acrobat Exchange used to open, _______________________________
navigate, note, search, link and copy and
paste from NDA review files _______________________________
_______________________________
____________________________

Slide 10 _______________________________
NEST
_______________________________
_______________________________
Let’s begin the NDA
Electronic Submission _______________________________
Review Training……..
_______________________________
_______________________________
_______________________________
____________________________

Chapter 2 - Accessing
Electronic submissions submitted to the Central Document Room (CDR) are placed on the
CDER network for access and review. Before reviewing these documents, reviewers must first
be able to access an NDA folder via the Electronic Document Room (EDR), save a drive path
(map), and copy the folders and files pertinent to their review discipline. This chapter will cover
how to search for a specific NDA via the EDR Intranet site. Once the drive path to the NDA
folder is found on the network, the path to the folder can then be saved and assigned a drive letter
(mapping.) Once the drive path has been mapped, a desktop shortcut to the NDA folder is
created to repeat the mapping steps each time a reviewer logs on to the network. Windows 95
tools can also be used to copy relative Electronic Submission files to a reviewer’s hard drive,
where notes and changes can be made to the files without affecting the integrity of the original
submission file.
Windows 95 file management tools and Microsoft’s Internet Explorer are used to complete the
tasks in this chapter.
This chapter will take about 30 minutes to complete.
NDA Electronic Submission Training – Chapter 2: Accessing electronic submissions 7

Electronic Document Room (EDR)
Once an NDA, Amendment, or Supplement has been placed on the CDER network, the location
of the submission files can be found via the Electronic Document Room (EDR). The EDR is a
Web based tool on the network that contains search capabilities for NDAs and their associated
Amendments and Supplements. Once you have an NDA number, access the EDR to find the
location of the submission files.
To access the EDR:
• Start MS Internet Explorer by double-clicking the icon on the Win95 desktop
• In the Address field, type EDR and press [ENTER]
The Electronic Document Room Web page appears.
• In the NDA Quick Search field enter the NDA number and press the Search button
Quick Search
Field
Exercise 2-1: Access the Sample NDA 123456
If the NDA number is valid, the NDA Application #, Trade Name, and Company Name will
appear for each submission. Type, Sequence #, Sup. Mod. Type, Stamp Date, Application Drive
Path (location on the network), and Comments will appear for the NDA and any associated
Amendments or Supplements.
NOTE: NDA, Amendment, and Supplement folders may look identical on the network. Use the
EDR to distinguish between the two.

NDA
Amendment
To access and display the contents of the main NDA folder, click on Click here for the respective
NDA, Amendment or Supplement. The next window displays a list of folders and files contained
in the electronic NDA. To view these read-only, electronic submission files, click on the PDF
icon or folder. When a PDF icon is clicked, Adobe Acrobat will launch and open the PDF file.
Proceed to Chapter 3 to learn how to use Adobe Acrobat to work with electronic submission
files.
Submission
Contents
Submission
Location
Note the NDA drive path, as it will be used in the next section.
Exercise 2-2: Display the Sample NDA 123456 from the Search Results window in
the EDR.

Map a Network Drive
Once you have obtained the drive path of the sample NDA, you can access (map) this path on
your desktop. Mapping will create a drive letter on your desktop, which allows easy access to
the NDA shared area.
To map to a network drive:
• Minimize any open applications
• Right-click on My Computer and click Map Network Drive
• Select a drive letter
• Enter the path to the NDA you found in the EDR (e.g., \\cds006\samplenda) in the
Path: field
• Check the Reconnect at logon box if you want to repeat this process every time you
log onto the network from this PC
• Click the OK button (you should now be mapped to the NDA shared area)
Exercise 2-3: Map the drive letter Z: to sample NDA 123456 and DO NOT
reconnect at logon.
Create a Desktop Shortcut

Once you have mapped the network drive, a window will open displaying the contents of the
shared area. You can create a shortcut on your desktop to quickly access the NDA folder without
having to map to the shared area each time you need access.
To create a desktop shortcut:
• Right-click and hold down on the NDA folder (e.g., N1234546).
• Drag the icon onto your desktop
• Lift your finger off of the mouse. A pulldown menu will appear.

• Highlight and click Create Shortcut(s) Here
• The shortcut appears on your desktop
Create
Shortcut
NDA
Folder
• To change the desktop shortcut label, right-click the shortcut and choose Rename. If you
are creating a shortcut to an Amendment or Supplement, make sure to include this
information when renaming the shortcut
Exercise 2-4: Create a desktop shortcut to the folder for sample NDA 123456 and
close the Samplenda on 'Cds006' (Z:) window
Copying Folders to Your Desktop

You can copy folders related to your discipline directly to your hard drive. This will allow you
to open, note, and make changes to the PDF review files which exist in that folder. Before you
copy the folder, you need to make sure you have available disk space:
• Open My Computer and right-click on the C: drive icon
• Choose Properties on the pulldown menu. Note the free disk space on the C: drive and
click OK.

Free Disk
Space
Used Space
Free Space
To check the size of the folder:
• Double-click on the NDA shortcut on your desktop
• Right-click on the Folder related to your discipline:
• Select Properties from the pulldown menu
• If the size of the folder you are copying is less than the space available on your C: drive,
continue to the next step. If the folder is larger, you will not be able to copy the folder to
your C: drive.
Folder Size
• Click OK
NOTE: It is recommended that you always keep at least 50mb available space on your hard drive
for optimum PC performance.

To copy the folder to your C: drive:
• Right-click on the folder related to your discipline:
• From the pulldown menu, select Copy
• Move your pointer onto the desktop and right-click. A pulldown menu will appear.
• Highlight and click Paste
Folder
Folder Copy
The folder now appears on your desktop.
You may also create a shortcut using the previous instructions.
Exercise 2-5: Check the size of the N123456\CMC folder and copy it to your
desktop. Close all open windows when complete.

Review
This chapter introduced you to accessing NDAs, Amendments, and Supplements via the
Electronic Document Room (EDR) to find review folders located on the network. You also
learned how to map and save the drive path on your desktop. The following chapters will cover
using Adobe Acrobat to open, navigate, create and modify annotations, and perform searches in
the Electronic Submission files you have just accessed. To test your knowledge of the topics
covered in chapter 1, answer the following questions:
• How do you access the Electronic Document Room (EDR)?
• How do you find the location of and NDA or Review using the EDR?
• How do you map to an NDA’s shared area location?
• How do you create a shortcut to the NDA?
• How do you copy NDA folders?
• How can I tell the difference between an NDA and an Amendment or Supplement?
• How much available hard drive space is recommended for optimum PC performance?

Chapter 3 - Exploring
In this chapter, you will learn the following:
• Access and view the NDA Table of Contents
• About Adobe Acrobat
• Compare labeling drafts
• Navigate a document using the buttons in the Adobe Acrobat toolbar.
• Change the magnification of a page view.
• Display and use Bookmarks
• Use the Find Tool
• Use the Search Tool
NDA Electronic Submission Training – Chapter 3: Exploring electronic submissions 17

Opening the Electronic Submission Table of Contents
Electronic submissions have a table of contents with links to all PDF files contained in the
submission. To access the electronic NDA Table of Contents:
• Access the NDA via the EDR or map to the NDA shared area
• Double-click the Ndatoc.pdf file found in the main NDA folder
Adobe Acrobat will launch with the Table of Contents open.
Looking At the Work Area

The Adobe Acrobat work area consists of the command menus at the top of the screen, the
toolbar containing various tools and button controls, the document window containing the active
document, and the informational status bar at the bottom of the screen.
Menu Bar Command

Bar
Palette Menu Document

Pane Menu
Tool Bar Document

Pane
Navigation Status Bar

Pane

Looking At the Status Bar
The buttons and menus in the status bar provide quick ways to change your on-screen display and
to navigate through documents.
A. Navigation Pane button B. Magnification level C. Magnification pop-up menu D. First Page button E. Previous
Page button F. Current page G. Next Page button H. Last Page button I. Page size J. Page Layout pop-up menu
Following A Link
The NDA table of contents contains links to a table of contents file for each main NDA folder.
These links make it easy for you to locate review data by discipline and navigate through the
document.
To navigate the NDA from the table of contents
• Click the hand tool ( ) and move the pointer over the desired section in the table of
contents. The pointer changes to a pointing finger icon (shown below), indicating that you are
positioned over a link.
• Click to jump to the link destination — the table of contents for that discipline.
Exercise 3-1: Open the table of contents for NDA 123456 and go to the Labeling
table of contents.
Compare Word
The Compare Word command compares the text content of text on corresponding pages in two
documents. Differences are identified by:
• If text does not match on the two pages, the text is highlighted on both pages.
• If text is found on only one of the pages, the text is highlighted on that page, and a triangle
marks the place on the corresponding page.
To compare text in two documents:

• Open two documents. The first document you open will be on the right in the
comparison file. The second open document will be on the left.
• On the menu bar, go to Tools | Compare Words. The two documents appear side by
side in a new, read-only comparison file.
First File
(right)
Compare File
Second File
(left)
The first page provides an overview of the text discrepancies found in the files. Scroll through
the new comparison file to see the actual changes (marked by highlighting and triangles).
Using the Browse Buttons

Use these browse buttons in the command bar:
• The Next Page button,
• The Previous Page button,
• The Last Page button,
• The First Page button,
Exercise 3-2: Compare the approved labeling with the proposed labeling file and
browse through the new compare words file. Browse back to the beginning and
then close the new file and proposed.pdf when you are done.

Retracing Your Viewing Path
In Acrobat, a view consists of a specific page and a specific magnification displayed on your
screen. Acrobat’s links and interactive features let you jump quickly and easily to different
views.
The Go To Previous View button, , is useful for retracing your viewing path through a
document, especially when you have followed a complex series of links and changed
magnification levels several times.
To retrace your viewing path:
• Click the Go To Previous View button, , in the command bar
• Click the Go To Next View button, , for each step forward
• To retrace your viewing path through other PDF documents, press [SHIFT] and click the
Go Back or Go Forward button. This command opens the other PDF documents if the
documents are closed.
You can click the Go Back button repeatedly to retrace your viewing path, view by view for up to
64 views, through a document. If you have followed a link to another PDF document, the Go
Back button can also return you to your original document.
Changing the View Magnification

When accessing electronic submission files, you can change the magnification of the page view
using built-in controls in the toolbar, or by clicking or dragging in the page with the zoom tool.
Magnification tools:
• To resize the page to fit entirely in the window, click the Fit In Window button,
• To resize the page to fit the width of the window, click the Fit Width button,
• To return a page to its actual size, click the Actual Size button,
• Click the zoom tool ( ) in the toolbar. You can either drag a rectangle around the area of
the page you want magnified (this is called marquee zooming) or you can click on an area of
the page to magnify.

Marquee
Zoom
Exercise 3-3: Navigate back to the NDA table of contents and go to the Summary
section of the NDA. Display the first page of the summary document at three
different magnifications - 100%, fit the whole page inside the main window, and fit
the width of the page inside the main window.
You can also use the magnification option on the status bar, , at the bottom of the screen
to change the magnification.
Using Bookmarks
A bookmark is a type of link in the navigation pane. Each bookmark in the navigation pane goes
to a different view or page in the document. As part of the comprehensive table of contents,
bookmarks are included in each PDF review document in an electronic NDA. When bookmarks
are included in the PDF review document, the navigation pane should automatically appear when
you open the review file.
To use bookmarks:
• Click the Show/Hide Navigation Pane button, , and then click the Bookmarks tab
• Move your pointer over a bookmark in the navigation pane and click to go that selection

Navigation Bookmarks
Pane
Exercise 3-4: Use the bookmarks to go to the Nonclinical Toxicology section of the
summary document. Go back to the first page of the summary document when
done.
Searching For A Word - the Find Tool

Adobe Acrobat gives you the following ways to search through a file or a collection of files for a
desired piece of information:
• The find tool lets you search through a single document for occurrences of a specific word or
phrase
• The search query tool lets you search for information in a collection of documents, using an
index that has been created in Acrobat Catalog
To use the find tool:
• Click the find tool ( ) in the command bar to display the Find dialog box. The Find dialog
box lets you enter the word or phrase you want to find.

• Selecting the Match Whole Word Only option displays all occurrences of the text as it
appears in the Find What field. The Match Case options allows you to look for words
in the same case. Find Backwards lets you search backward starting from the current
page in the document.
• Click the Find button to begin the search.
• To repeat your find, click the find tool ( ) and press the Find Again button to search
again.
Exercise 3-5: Find the patient deaths in the summary document using the Find tool.
The find tool in Exchange suffices when you want to search for a word or phrase in a single
document. For more sophisticated searching of multiple documents at once, you can use the
Search command.
Searching For Words and Phrases in the Indexes

The Find Tool is beneficial when searching for one word or one group of words in one file.
However, you can also perform a search over multiple files at once. Each section of an
electronic submission will be cataloged. Each folder in an electronic NDA will have an index, a
PDX file, which contains a complete listing of the all the text in all the files in that particular
folder.
To search a NDA folder, you first must add the folder’s index files, PDX files, to the index list
using the Search Query tool ( ).
To add indexes:
• Click the Search Query Tool ( )
• Click the Indexes button
• Remove any existing indexes by:
– Clicking on them
– Clicking on the Remove button
• Click the Add button

Available
Indexes Add Button
• Navigate to and find the folder you want to search
• Click on the index file (e.g., crfindex.pdx, and click Open)
• Click OK
Once you have added the index of the folder you want to search, you can now search the
discipline's folder for a simple word or phrase, search fields associated with each file, or you can
expand your search query by using wild-card characters and operators.
To perform a full-text search:
• Type the text you want to search for in the Find Results Containing Text box
• Click the Search button
If a match is found, the file will appear in the document pane. If multiple files match you search,
the Search Results window appears. Click the View button to open the PDF file. Click the
Info… button to find information related to the location, author, and history of the electronic
submission file.
You can also use the Search Results ( ) button on the toolbar to bring back the Search Results
window. Use the Search Next and Search Previous buttons ( ) to go to other

matches in your search. Close the Search Results window by clicking the (X) in the top right
corner.
To search document information fields:
NDA PDF files also contain valuable information stored with each file in the document
information fields. These fields contain important, searchable information about that file.
Sponsors are asked to include information such as patient ID numbers, site number, studies, etc
in these fields.
In order to display the document information fields in the search window:
• Go to File | Preferences | Search
• Click the first box, Show Fields
• Click OK
Use these fields to search for text associated with that document. The table on the following
pages outlines what you can expect to find in the document information fields for the PDF files
located in electronic NDAs.

Folder Document Information Information
Field
Table of Contents NA NA
Labeling Title brand name
Subject generic name
Author applicant, applicant’s label code
Keywords NDA number, approval status, date of

labeling. For drafts - changes being
affected. For annual report changes - date
of submission. For approved labeling - date
of approval.
Summary NA NA. Not indexed.
CMC Title
drug substance files ds, the name of the active ingredients, brief
description of the document (limited to a
couple of words)
drug product files dp, the name of the drug product, brief
description of the document
Environmental assessment ea, name of the drug product, brief

description of the document
Nonclinical Pharmacology and Title

Toxicology
Summary document summary should be identified as pharmtox

summary (clarified)
each study report Designated study and followed by the study

report number and the study type. Helpful
information may also be included, such as
the species and treatment duration (e.g.,
study 2001, toxicity study, dog, 12 month)
animal line listing files the word data should also be added
Human Pharmacokinetics and Title

Bioavailability
summary document for the identified as cpbio summary (clarification)

clinical pharmacology and
biopharmaceutics
Study Subfolders type of study (e.g., biopharm, pk, pd,

subpops, drugint, invitro, assay, pubs) and
the study number

Folder Document Information Information
Field
Clinical Microbiology Title
summary document Identified as micro summary (clarification -

how should they be identified?)
Studies type of study and the appropriate reference

number
Clinical Title
study reports brief description of the document, usually

consisting of a couple of words. Includes
the study number as a description
Safety Update NA NA
Statistical Section Title
Study reports brief description of the document, usually

consisting of a couple of words. Includes
the study number as a description
Case Report Tabulations (CRTs) Title
patient profiles organized by site pp, the study number, the site identification
and the patient’s unique ID number
patient profiles organized by pp, the study number, and the site
study identification
patient profiles organized by pp and the study number

patient
domain profiles organized by dp and the study number

study
domain profiles organized by dp, the study number and the appropriate
domain CRF domain name
Case Report Forms (CRFs) Title
case report forms organized by crf and the study number

study
case report forms organized by crf, the study number and the site
site identification
case report forms organized by crf, the study number, the site number and
case report form the unique patient ID number

Searching with Wild-Card Characters
When entering text in the document information fields, the full text character string may not be
known. Wild-card characters can be used to find all the words that contain a word fragment or
all the terms that match an arbitrary character pattern:
• (*) asterisk, matches zero, one, or more characters
• (?) question mark, matches any one character
You can use wild-card characters in a term that is part of a Boolean expression. You can also use
wild cards to specify Document Info field values. You cannot use wild cards to represent
separator characters such as the hyphen [-] and the slash [/].
Searching with Boolean Expressions
You can use AND, OR, and NOT operators to build a Boolean expression that will search for
specific words. Using AND between two words returns only documents containing both words.
NOT before a word excludes documents containing the word or search term. Use OR between
two words to return documents containing either word.
Search
Options
Search Options
The options in the Search window expand or limit the results of searches:
• Word Stemming finds words that share a stem with the search word.
• Thesaurus finds words that have similar meanings

• Sounds Like finds different spellings of proper names.
• Match Case finds text only when it has the same capitalization as the text you type
• Proximity searches so that words must be within three pages of each other.
Exercise 3-6: Search the CRF index for any file related to 1) patient0000 and 2)
patient 1111 or any patients that start with the numbers 23.

Review
This chapter introduced you to the basic navigational techniques and interactive elements that
you can use within an electronic NDA. The following chapters and projects provide in-depth
instructions for working with NDA PDF files that you copy to your hard drive, as well as finding
support for electronic submissions.
To test your knowledge of the concepts and techniques you learned in this chapter, answer the
• How do you return to a previous view of an Electronic NDA document?
• How do you navigate to the last page?
• What is the difference between the Find tool and the Search command?
• How do you add Indexes to your search?
• What features are displayed in the navigation pane?
• What is a Boolean expression?
• How do you navigate using ndatoc.pdf?

Chapter 4 – Electronic Review
Tools
In this chapter, you’ll learn how to do the following:
• Create and view annotations
• Create and annotate mark up tools
• Summarize Annotations
• Copy and Paste Text
• Copy and Paste Tables
• Copy and Paste Graphics using the ISI Graph Copy Plus lug-in
NDA Electronic Submission Training – Chapter 4: Electronic Review Tools 33

Annotations
Annotation tools let you add comments anywhere on a page in an PDF review document
to communicate review comments, last-minute information to others, or personal
information to yourself. Two types of annotations are optimal for annotating review
documents - the Notes tool and the Text Annotation tool.
NOTE: Since the NDA files on the network are read-only, copy the file you wish to annotate to
your hard drive, network share, or floppy disk before creating notes. Click the save button, ,
on the command bar to save annotations to your copy of the PDF file.
To add a note annotation:
• Select the notes tool,
• Click the location where you want to place the note, or drag to create a custom-sized
window. The maximum size for the note window is 288 pixels high and 432 pixels wide
• Click inside the window, and type the text for the note
Note
Window
• Click the minus bar, , in the upper left corner of the window to close a note
While a note can be closed, a text annotation remains visible above the text or image in a PDF
document.
To add a text annotation:
• Click and hold down on the note annotation tool
• Holding down on the mouse, drag to the right to select the Text Annotations tool,

Text
Annotation
• Click where you want to place the text annotation, or drag a rectangle to create a text field
• Enter your annotation
• Click outside of the text field to close
Graphic Markup Tools

Markup tools are available on the Acrobat toolbar beneath the Annotations tools. Markup tools
visually annotate a PDF review document with free form pencil lines, rectangles, ellipses, and
straight lines. Notes can also be attached to better define the marked text.
To draw with the pencil tool:
• Click the pencil tool, , in the toolbar
• Move the cursor where you want to begin drawing. The graphic does not have to be one
consistent stroke. You can let go and draw in as many places as desired.
• Select the hand tool, , when finished
To annotate the pencil markup:
• Annotating PDF Documents
• Move the cursor over a the pencil line until the cursor changes to a double-headed arrow and
double-click to open the notes window

Note Double-
Window headed arrow
• Type in your text note
To use the line, rectangle, or ellipse tool:
• Click on the pencil tool and drag to the right
• Select the line, , rectangle, , or ellipse, , tool
Rectangle
Tool
Line Tool
Ellipse Tool
• Click a start point, hold down the mouse button and drag the object to your desired size. Let
go of the mouse when done
• Click and drag to move the object around the page or change its size, if necessary
To associate an annotation:
• Double-click the markup object
Text markup tools
Text markup tools can be used by themselves or in with other annotation types. The types of
markups allow you to highlight, strike through, or underline text.

To use the text markup tools:
• On the toolbar, select the highlight text tool, , or click and drag to the right to select the
strikethrough text tool, , or the underline text tool,
• Click and drag over the selected text
NOTE: The printed version of a document marked up with highlighted text looks different from
the screen version. Text that is highlighted on-screen prints with a box around it
To associate an annotation:
• Double-click the markup object
Delete, Change Preferences For, Or Change Individual

Properties For Notes And Markup Annotations:
To delete, change preferences for, or change individual properties for notes and markup
annotations:
• Right-click on the closed noted, then choose the desired option from the menu
or
• Click on the object and go to Edit | Properties on the menu bar

Exercise 4-1: Put a square around the three paragraphs at the top of page 266 of
the N123456 summary document and leave a text note that reminds you to copy the
paragraphs into your review. Circle the third paragraph and leave a text note that
states there was no investigator report. Highlight the table on page 265 and leave a
text note reminder to copy the table into your review. Save your annotations.
Summarize Annotations
Summarize Annotations
When you add annotations to your file, you may create a summary PDF file of all the notes
contained in the PDF file. The summary arranges the annotations in order as they appear in the
file with note #, label, create date and time, and full text content.
To create a note summary:
• Go to Tools | Annotations | Summarize Annotations
A new PDF file will be created (e.g., Notes from ndatoc.pdf). You may wish to save these files
on your hard drive or close them without saving.
Annotation Scan
You can also display annotations in the navigation pane on the Annotations palette. Using
the annotation scan feature will allow you to create, or update, a list of annotations in the current
file. The items in the list also contain hyperlinks to that annotation location in the file.
To perform an annotation scan:
• Click on the Annotations tab in the Navigation Pane
• At the bottom of the Navigation Pane, click on the Start Annotation Scan, , button
• Click the Save button

Annotation Hyperlinks
Scan
Exercise 4-2: Summarize your annotations for the summary document in a new file,
then close the file. Summarize your annotations in the Navigation Pane. Save your
file.
Copy and Paste Text

Text from a review document may be copied from PDF files and pasted to other applications
such as Microsoft Word or TeamLinks. However, when using the default text select tool in
Acrobat, the pasted text retains the line breaks that appeared in the PDF file. In order to paste
text into applications that will fill the margins, the table/formatted text select tool must be used.
The table/formatted text select tool allows you to select tables and text in a PDF document and
retain the original formatting when the material is copied (or imported) into other applications.
You can specify vertical or horizontal format, the type of text flow, and whether you want ANSI
(simple text) or Rich Text Format (RTF).
Before copying and pasting text into another application, a preference needs to be changed in
Acrobat. The indentation paragraph formatting preference must be turned off to allow the pasted
text to fill the margins in the destination file.
To turn off the indentation paragraph formatting:
• On the Menu bar, go to File | Preferences | Table/Formatted Text
• Click the RTF Export tab
• Uncheck the Indentation box
• Click OK

To copy and paste formatted text:
• On the tool bar click on the text select tool, , and drag to the right and select the table/
formatted text select tool,
• Click and drag a box around the desired text
• Make sure the type is Text-Flow (If not, right-click in the paragraph and choose Text |
Flow from the popup menu)
• On the menu Bar, go to Edit | Copy
• Go the destination application (e.g., Microsoft Word)
• On that application’s pulldown menu, go to Edit | Paste or click the paste button on the
toolbar
Exercise 4-3: Change the Acrobat formatted text preferences to remove indentation
paragraph formatting when exporting. Copy the three paragraphs on page 266 of
the summary document to a Microsoft Word document.
Copy and Paste Tables

The same tool that is used to copy formatted text is also used to copy and paste tables from PDF
to other applications. Tables copied from PDF maintain the original format of the table,
preserving the data as rows and columns of cells.
To copy and paste a table:
• On the tool bar click on the Text Select Tool, , and drag to the right and select the Table/
Formatted Text Select Tool,

• Click and drag a box around the table
• Make sure the type is Table (If not, right-click in the table choose Table from the popup
menu)
• On the Menu bar, go to Edit | Copy
• Go the destination application (e.g., Microsoft Word)
toolbar
If you are using Microsoft Word
Additional cells may be created when the table is pasted. Follow the directions below to merge
the extra cells and recreate the PDF table:
• Select the table
• Click the borders button, , on the Formatting toolbar
• Use the eraser tool, , or the merge cells tool, , to remove the excess borders
Exercise 4-4: Copy the table on page 265 of the summary document to a Microsoft
Word document. Put borders on the table.

Copy and Paste Graphics
Graphics that appear in PDF files can be copied to other applications used in the review process.
In order to capture the best resolution of the graphic, an additional plug-in, ISI Graph Copy Plus,
is included in the standard CDER install of Acrobat 4.0. ISI graph Copy Plus copies the graphic
from the PDF file and pastes it as a bitmap image.
Although Acrobat does contain a graphic copy tool, use the ISI Graph Copy Plus when
copying and pasting graphics from PDF to other applications. Follow the directions below
to copy and past graphics using the ISI Graph Copy Plus plug-in.
NOTE: In order for the ISI Graph Copy Plus plug-in to work, your monitor color palette must be
set to 256 color. To check this setting, go to Start | Settings | Control Panel and
double-click on the Display icon. Click the Settings tab. If you need to change the color
palette to 256 color, close all programs first as the change will require you to restart your
computer.
To copy and paste graphics:
• On the tool bar, select the ISI Graph Copy Plus button,
• Click and drag a box around the graphic
• When you let go of the mouse, wait a few moments until the box disappears
ISI Graph
Copy Plus Selection
Box
The ISI Graph Copy Plus plug-in automatically copies the graphic to the clipboard so there is no
need to use the copy feature in Acrobat.
• Go to the destination application (e.g., Microsoft Word)
toolbar

If you are pasting into a Microsoft Office application and do not wish the graphic to “float” over
text, follow these directions to paste the graphic:
• On the pulldown menu, go to Edit | Paste Special
• Uncheck the Float over text box
• Click OK
Exercise 4-5: Copy the scatter plot on page 242 of the N123456 summary document
to a Microsoft Word document as a graphic that does not float over text.

Review
In this chapter, you learned how to work with notes, control the number of open windows,
change page views, and copy and past text and graphics. In the last chapter, you will learn how to
find Support when you have questions related to electronic submissions and Adobe Acrobat.
To test your knowledge of the concepts and techniques you learned in this chapter, answer the
• What tool is used to copy text and tables?
• What are the different types of graphic markup tools?
• Can you save notes on the network copies of the electronic submissions files?
• What table/formatted text preference needs to be changed before copying text?
• Where do you find the ISI Graph Copy Plus tool?
• What color palette setting is required to use ISI Graph Copy Plus?
• What Microsoft Word feature allows you to paste graphics that do not “float” over text?

Chapter 5 – Support
Now you are ready to go and work on electronic submissions. But what happens when you have
a question or forget something covered in class? When should the Help Desk be called and what
sort of information do you need to provide them to help find an answer?
It is likely that a person who can find an answer to their question on their own will not have that
same question again. This chapter covers how to find answers independently and how and when
to access additional technical and peer support.
This short chapter will instruct you how to access the following types of support in the Center:
• Classes and Manuals
• Adobe Acrobat Online Guide
• Acrobat Preferences
• OIT Support
• Peer Support
NDA Electronic Submission Training – Chapter 5: Support 47

Classes and Documentation
Class and Course Evaluation
The NDA Electronic Submissions Training (NEST) class offered by OIT is dependent upon you
to make constructive insights and comments on the course. Please make sure to fill out and
return the OIT Course Evaluations at the end of class. These evaluations will help us shape the
class so it is most beneficial to review staff.
Manual and Draft Guidance
The NEST manual can be found on the OIT Web (HTTP://OITWEB/OIT) under the
Documentation/ Applications Training section. PDF copies of the NEST manual
and draft Guidance can be copied to your hard drive or floppy disk.
Trifolds
Quick reference desktop trifolds for Adobe Acrobat and NEST are provided in class or can be
accessed and downloaded from the OIT Web. Use these trifolds for answers to frequently asked
questions.
Adobe Acrobat Online Guide

NDA Electronic Submissions Training (NEST) introduces CDER staff to the features available
in Adobe Acrobat 4.0. Additional information on the features discussed in this course, as well as
Acrobat features not covered in this manual, can be found in the Acrobat Guide.
To access the Acrobat Guide:
• Go to Help | Acrobat Guide on the menu bar
The Acrobat Guide will appear. Use the links on the front page or go to the index and the end of
the file to browse topics alphabetically.

Exercise 5-1: Look up information about page layouts in the Acrobat Guide.
Acrobat Preferences
In order to utilize Acrobat in the electronic review environment and customize features for your
use, preference changes can be made in Adobe Acrobat. Use the File | Preferences feature on the
menu bar to change preferences for text and tables, annotations, page layouts, web integration,
and other tools. Several preference changes are listed in this manual and the documentation
provided when you install Adobe Acrobat from the OIT Web.
OIT Support
If you are unable to find the answers you need via class instruction, manuals, or the Acrobat
Guide, please call the Help Desk at X7-0911 or e-mail them at HELPDESK. Please indicate
whether your problem is related to Adobe Acrobat or electronic submissions (e.g., missing NDA
folder).
Peer Support
Some of the best resources for learning are those who work with us every day. Those of you who
have taken the NEST course and have a firm grasp of the electronic submissions process can help
share your expertise with others by acting as a mentor to those seeking information and feedback
to their ERSR related situations. Look for a more formalized peer support system as more Center
staff become familiar with NEST and ERSR regulations.

Appendix - Exercise Solutions
Use this appendix to find the answers to the classroom exercises found throughout the manual.
NDA Electronic Submission Training – Appendix - Exercise Solutions 51

Exercise 2-1: Access the Sample NDA 123456
• Start MS Internet Explorer by double-click the icon on the Win95 desktop
• In the Address field, type EDR and press [ENTER]
The Electronic Document Room Web page will appear.
• In the NDA Quick Search field, remove the 0, enter the sample classroom NDA number,
987654 (Actual NDAs begin with 0) and press the Search button
Exercise 2 -2: Display the Sample NDA 123456 from the Search Results window in
the EDR.
• Click on Click here for NDA 123456
Exercise 2-3: Map the drive letter Z: to sample NDA 123456 and DO NOT
reconnect at logon.
• Minimize any open applications
• Right-click on My Computer and click Map Network Drive
• Select Z as the Drive letter and enter \\cds006\samplenda in the path field
• Make sure the Reconnect at logon box is not checked
• Click the OK button (you should now be mapped to the sample shared area)
Exercise 2-4: Create a desktop shortcut to the folder for sample NDA 123456 and
close the Samplenda on 'Cds006' (Z:) window
• Right-click and hold down on the n987654 folder.
• Drag the icon onto your desktop
• Lift your finger off of the mouse. A pulldown menu will appear.
• Highlight and click Create Shortcut(s) Here

• To change the desktop shortcut label, right-click the shortcut and choose Rename. If you
are creating a shortcut to an Amendment or Supplement, make sure to include this
information when renaming the shortcut
• Close the Samplenda on 'Cds006' (Z:) window
The shortcut appears on your desktop.
Exercise 2-5: Check the size of the N123456\CMC folder and copy it to your
desktop.
To check the size of the folder:
• Double-click on the Shortcut to N987654 icon on your desktop
• Right-click on the CMC folder
• Select Properties from the pulldown menu
• If the size of the folder you are copying is less than the space available on your C: drive,
continue to the next step. If the folder is larger, you will not be able to copy the folder to
your C: drive. Click OK
To copy the folder to your C: drive:
• Right-click on the CMC folder
• From the pulldown menu, select Copy
• Move your pointer onto the desktop and right-click. A pulldown menu will appear.
• Highlight and click Paste
• Close My Computer and the shortcut windows.
The folder now appears on your desktop.
Exercise 3-1: Open the table of contents for NDA 123456 and go to the labeling
table of contents.
• Double-click the Shortcut to N987654 shortcut on your desktop
• Double-click the Ndatoc.pdf file.

• Click the hand tool ( ) and move the pointer over the Labeling section of the Table of
Contents. The pointer changes to a pointing finger icon (shown below), indicating that you
are positioned over a link.
• Click the Labeling text to jump to the link destination—the Table of Contents for the
Labeling folder.
Exercise 3-2: Compare the approved labeling with the proposed labeling file and
browse through the new compare words file. Browse back to the beginning and
then close the new file and proposed.pdf when you are done.
• Click the last approved labeling link in the labeling table of contents
• Click the Open button, , on the command bar
• Double-click on the labeling folder
• Double-click on the proposed.pdf file
• While both files are open, go to Tools | Compare Words on the Acrobat menu bar
A new file titled Compare Words proposed.pdf : appoved.pdf appears listing the
changes found in comparison of the two documents
• Click the Next Page button, , to scroll and see how the documents differ
• Click the Last Page button, . You are now at the end of the document
• Click the First Page button, , to return to the start of the document
• Close the new compare and proposed.pdf files
Exercise 3-3: Navigate back to the NDA table of contents and go to the Summary
section of the NDA. Display the first page of the summary document at three
different magnifications - 100%, fit the whole page inside the main window, and fit
the width of the page inside the main window.
• Click the Go to Previous button, , twice to go back to ndatoc.pdf
• Click on Summary in the table of contents
• Click on the Actual Size button, , to change the magnification to 100%

• Click on the Fit in Window button, , to fit the whole page inside the window
• Click on the Fit Width button, , to fit the width of the page in the window
You can also use the magnification option on the status bar, , at the bottom of the screen
to change the magnification.
Exercise 3-4: Use the bookmarks to go to the Nonclinical Toxicology section of the
summary document. Go back to the first page of the summary document when
done.
• If the overview window is not displayed, click the Show/ Hide Navigation Pane button, ,
or the Navigation Pane button, , at the bottom of the screen
• Click the Bookmark tab
• Highlight and click on the H. Nonclinical Toxicology bookmark
• Click the First Page button ( I!) to return to the start of the document
Exercise 3-5: Find the patient deaths in the summary document using the Find tool.
• Click the find tool ( ) in the command bar to display the Find dialog box. The Find dialog
box lets you enter the word or phrase you want to find.
• For Find What:, enter death
• Select the Match Whole Word Only option. Selecting this option displays all occurrences of
“death” only as it appears. The Match Case options allows you to look for words as they
appear. Find Backwards lets you search backward starting from the current page in the
document.
• Click the Find button to begin the search.
The word “death” appears towards the bottom of page 47 but it does not relate to deaths specific
to this submission. To look for the word “death” in the rest of the document, use the Find Again
option.
• To repeat your Find, click the find tool ( ) and press the Find Again button to search
again. As you can see the word “death” appears again on page 265 of the Summary
document. Three deaths related to this submission are listed. It is noted to look in the case
report form section for information on two of the deaths.

Exercise 3-6: Search the CRF index for any file related to 1) patient 0000 and 2)
patient 1111 or any patients that start with the numbers 23.
1) Patient 7839
• Type the first patient ID# – 0000
• Click the Indexes button
• Remove any existing indexes by clicking on them, then clicking on the Remove button
• Click the Add button
• Navigate to and find the crf folder
• Click on the index file, crf.pdx, and click Open
• Click OK
• In the Search window, click the Search button
• You will receive the message – No documents were found that matched your query.
Expand the search to the document information fields:
• Go to File | Preferences | Search
• Click the first box, Show Fields
• Click OK
• Enter 0000 in the Title section of the Document Information Field
• Click Search again.
2) Patient 0000 or any patient starting with the numbers 23
• Put a comma (,) after 0000 (you can also use the Boolean expression OR instead of the
comma)
• Add the second patient ID number and type, 23*
• Click the Search button.

Exercise 4-1: Put a square around the three paragraphs at the top of page 266 of
the N123456 summary document and leave a text note that reminds you to copy the
paragraphs into your review. Circle the third paragraph and leave a text note that
states there was no investigator report. Highlight the table on page 265 and leave a
text note reminder to copy the table into your review. Save your annotations.
Rectangle Annotation:
• On the Menu Bar, go to File | Save As
• Save the summary document to the C:\Classes\NEST folder (The network copy is read-
only)
• In the current page section of the status bar, type 266 and press [ENTER]
• On the tool bar, press and hold down on the pencil tool, . Drag to the right and select the
rectangle tool,
• Click and drag a rectangle around the first three paragraphs on the page.
• Move your pointer on the rectangle so the arrow, ", appears and double-click
• Type in your note and click the minus bar to close the note field
Pencil Annotation:
• On the tool bar, press and hold down on the rectangle tool. Drag to the right and select the
pencil tool
• Click and draw a circle around the third paragraph.
• Select the hand tool
• Move your pointer on the line around the third paragraph so the arrow, ", appears and
double-click
Highlight Text Annotation:
• Click the Previous Page button
• On the tool bar, click Highlight Text button,
• Click and drag over the text in the table at the bottom of the page.
• Move your pointer on the line around the table until the arrow, ", appears and double-click

• Select the Hand Tool
Save the file to a local drive:
On the menu bar, go to File | Save As
Save Summary.pdf in the C:\Classes\NEST folder
Exercise 4-2: Summarize your annotations for the summary document in a new file,
then close the file. Summarize your annotations in the Navigation Pane. Save your
file.
Summarize Annotations:
• On the menu bar, go to Tools | Annotations | Summarize Annotations
• After reviewing, close the summary file without saving
Annotation Palette:
• Click on the Annotations tab in the Navigation Pane
• At the bottom of the Navigation Pane, click on the Start Annotation Scan button
• Click the Save button
Exercise 4-3: Change the Acrobat formatted text preferences to remove indentation
paragraph formatting when exporting. Copy the three paragraphs on page 266 of
the summary document to a Microsoft Word document.
• On the Menu bar, go to File | Preferences | Table/Formatted Text
• Click the RTF Export tab
• Uncheck the Indentation box
• Click OK
• Navigate to page 266
• On the tool bar click on the Text Select Tool, , and drag to the right and select the Table/
Formatted Text Select Tool,
• Click and drag a box around the three paragraphs

• Make sure the type is Text-Flow (If not, right-click in the paragraph and choose Text |
Flow from the popup menu)
• On the Menu Bar, go to Edit | Copy
• Launch Microsoft Word
• On the pulldown menu, go to Edit | Paste or click the Paste button, , on the Toolbar
Exercise 4-4: Copy the table on page 265 of the summary document to a Microsoft
Word document. Put borders on the table.
• Go back to Adobe Acrobat
• Navigate to Page 265
• Click the Formatted Text Select Tool,
• Click and drag a box around the table
• Make sure the type is Table (If not, right-click in the table choose Table from the popup
menu)
• On the Menu bar, go to Edit | Copy
• Go back to Microsoft Word
• On the pulldown menu, go to Edit | Paste
• Select the table
• Click the borders button, , on the Formatting toolbar
• Use the eraser tool, , or the merge cells tool, , to remove the excess borders
Exercise 4-5: Copy the scatter plot on page 242 of the N123456 summary document
to a Microsoft Word document as a graphic that does not float over text.
• Go back to Adobe Acrobat
• Navigate to page 242 of the Summary document
• On the Tool Bar, select the ISI Graph Copy Plus button,
• Click and drag a box around the scatter plot

• When you let go of the mouse, wait a few moments until the box disappears
• Go to Microsoft Word
• On the pulldown menu, go to Edit | Paste Special
• Uncheck the Float over text box
• Click OK
Exercise 5-1: Look up information about page layouts in the Acrobat Guide.
• On the menu Bar, go to Help | Acrobat Guide
• Use the index to search for Page layouts. Click the last page button, , on the command
bar
• Make sure the hand tool is selected and click the P hyperlink on the right hand side of the
page
• Page layouts will appear at the bottom of the page and the categories with links can be found
on the next page. Click the next page button, , on the command bar
• Click on the for document viewing 41-43 link at the top left of the page. Browse
through the topic

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eCTD Di

Introduction by Emily Ethridge, Editor, FDAnews

Section 1.0 eCTD Tutorial Table of Contents.

Section 1.1 eCTD Module 1.

Section 1.3 Ensuring an Effective Submission.

Section 1.4 Guidance Compliant eCTDs Module 4.

Section 1.5 Guidance-Compliant eCTDs- Module 5.

Section 1.6 eCTDs Quality CMC Issues.

Section 1.7 Prequel Template or Guidance.

Section 03 Structure and Content of Clinical Study Reports.

Part 4 Technical Requirements.

Section 6 Comprehensive eCTD Table of Contents Headings and Hierarchy.

Section 7 Conformance Review Checklist For NDAs.

Section 8 eCTD Backbone Files Specification for Module 1.

Section 9 eCTD Backbone Files Specification for Modules 2 through 5.

Section 10 eCTD Backbone Files Study Tagging Files.

Section 11 eCTD Change Control Process v1.8.

Section 13 eCTD Specification v 3.2.

Section 14 eSUBS and eCTDs: Practical Advice and Pitfalls to Avoid.

Section 16 Future of Case Report Tabulation Submissions.

Section 17 Granularity Document Annex M4 Organization of the CTD.

Section 18 ICH eCTD Specification Document DTD 3.2.

Section 19 Module 1 Document Type Definition File.

Section 21 Portable Document Format Specifications.

Section 22 Specification for Transmitting Electronic Submissions using eCTD Specifications.

Section 23 Standards and Successful Document Creation.

Section 24 Study Tagging File Workshop.

Section 25 Transformation of the Backbone from XML to HTML.

Section 27 NDA Electronic Submissions Training.

The FDA is looking towards moving to an all-electronic submissions system for

The agency ultimately wants to create an electronic information exchange network to

Electronic submissions can be particularly helpful for companies considering a clinical

Another guidance provides recommendations on compiling a single core clinical study

To help with submissions, the book provides a presentation on providing regulatory

Another PowerPoint presentation explains how to differentiate between ICH guidelines

The second part provides step-by-step instructions on how to review submissions in

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

1. eCTD: Module 1, Bronwyn Collier, FDA

312.23 Cover sheet (Form 1 1.1.1 Application

314.50(h) Patent Information 1 1.3.5.1 Patent

FDA Overview of the eCTD

o Preferred format for submissions.

Gary M Gensinger, MBA

• Providing Regulatory Submissions in

• Providing Regulatory Submissions in

• XML-based eCTD Backbone replaces PDF Tables of Content

• Data files submitted in SAS XPORT

• Initial Pilot Phase

• No paper unless required for original

• CDER Contact for information on eCTD

Ensuring an Effective Submission

Gary M Gensinger, MBA

• One of your goals is communication

• Schedule prior to assembling

• Initiate contact prior to assembling

– Each and Every eCTD Requires Module 1

– MD5 Checksum values should be

• Useful to have a bookmarks back to

• Take advantage of FDA’s help before