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o
One section contains all information to perform in-depth clinical pharmacology and clinical/
statistical BLA/NDA review.
Permits comprehensive clinical pharmacology, clinical, statistical reviews.
Majority of IND/BLA/NDA clinical content in section 5.3.
A study report now comes in multiple files (E3) *different from the past.
Datasets and CRFs organized by study, but still XPT and PDF, respectively.
Introduction
By Emily Ethridge, Editor, FDAnews
The FDA is looking towards moving to an all-electronic submissions system for
regulatory information in all of its divisions to facilitate easier reviews and information
sharing. All submitted documents, such as new drug applications and marketing
materials, will come in electronic common technical document (eCTD) form.
Having data in a common electronic environment will allow the FDA to regulate
products quickly, eliminating difficulties with accessing, searching through and finding
data in paper forms.
The agency ultimately wants to create an electronic information exchange network to
share with the public, so that information can be traded between the FDA, investigators,
healthcare professionals, patients and other agencies.
Different product areas are in different stages of electronic submission requirements, and
changes will come in stages to each area. That is why it is essential for companies to
learn the details and standards for each type of electronic submission. Already the Center
for Drug Evaluation and Research has set a deadline for all submissions to arrive in
eCTD form.
While electronic submissions help the agency speed reviews and share information, they
also help companies. Using the eCTD costs less for companies than paper submissions,
freeing up resources that allow drugmakers to focus on interpreting clinical data instead
of handling that data.
Electronic submissions can be particularly helpful for companies considering a clinical
trial for a new indication of an approved drug, because it makes subsequent
communication with the FDA easier, more efficient and faster. Electronic submissions
create information collection mechanisms that make it easier for investigators to access
and interpret new data.
In this book, you will learn the benefits of switching to eCTD and the best practices for
the new format, as well as the specifications, standards and checklists for creating an
eCTD protocol in your company.
When the FDA held a public meeting on electronic submissions in December 2006,
several speakers noted challenges in switching to an electronic system, such as a current
lack of trained labor and standardized procedures. This book will help you navigate the
many FDA-issued documents to find the most valuable information so your company an
make a smooth transition to electronic submissions.
The book begins with a tutorial of seven PowerPoint presentations giving an overview of
the FDAs eCTD guidance document and how it will be implemented. The presentations
A PowerPoint presentation explains how to deal with two common study tagging file
problems using a maximum of 256 characters and computer displays that cannot
display lengthy path and file names.
Another presentation in this section provides practical advice and pitfalls to avoid for
submitting an electronic document, including referencing all files in the XML backbones
and using standard XML components.
Another PowerPoint presentation explains how to differentiate between ICH guidelines
and FDA requirements, how to identify goals and strategies for both industry and
regulators.
This section also includes a sample form for requesting a change to the ICH eCTD
specification, which can be used to fix a bug or to meet new requirements. In addition,
there is a document describing the parts of the registration application common to all
regions and some of the lifestyle requirements for products, and another establishing the
change control process for the eCTD specification.
The section also provides the specifications for submitting documents in PDF and for
transmitting electronic submissions using eCTD specifications either electronically or on
physical media. It also contains a document detailing where to place the integrated
summaries of safety and effectiveness in applications submitted in eCTD format.
Part Five of the book deals with training and preparing your company for switching to
submissions in eCTD form. The first part covers new drug application electronic data
analysis training, created by the FDAs Office of Information Technology along with
review staff. The training covers a guidance from the Center for Drug Evaluation and
Research (CDER) for sponsors to send case report form tabulations and individual animal
line listings as data sets.
The second part provides step-by-step instructions on how to review submissions in
electronic format. Currently at CDER, only new drug applications and their
corresponding amendments and supplements are received in electronic formats. Before
staff can review the submissions, the employees must first be able to access an electronic
submission folder on the network, save a drive path, copy the pertinent files and folders
and learn to use the features available in Adobe Acrobat.
Although the FDA may not be prepared to make a full switch to electronic document
formats right away, it is clearly trying to forge a path ahead to reach its ultimate goal of
all-electronic submissions. The agency has detailed its specifications, checklists,
definitions and objectives. With these tools and other industry documents, your company
can keep up with every detail and request in the process of switching to electronic
document formats.
Part 1
Tutorial
SECTION 1.0
This tutorial will provide an overview of FDA's eCTD guidance document and a comprehensive
discussion on preparing the five modules of an eCTD. Emphasis will be placed on ensuring the
successful submission of an application and facilitating the review process.
1.
2.
3.
4.
5.
6.
7.
SECTION 1.1
eCTD Module 1
eCTD: Module 1
Bronwyn Collier, Associate Director for Regulatory Affairs
Office of Drug Evalaution III
Center for Drug Evaluation and Research
FDA
April 2005
Module 1: Topics
Purpose
Impact on review process
Module 1 table of contents
Module 1: Purpose
Archive regional documents
Application management
Status
Business
Special regulatory programs
Provides the legal and regulatory framework
for the application/submission
Review assignment
Guides response
Satisfies some regulatory requirements
TOC Mapping
CFR Citation
eCTD/STF Heading
NUMBER
TITLE
312.7(d)
1.12.2
Request to
Charge
312.10
Waivers
1.12.5
Request for a
waiver
312.23
(a)(1)
1.1.1
Application
form: FDA form
1571
N/A
N/A
N/A
1.3.5.1
Patent Information
MODULE NUMBER
TITLE
Patent
Information
5
Module 1 TOC
1.1 Forms
1.1.1 Application form: FDA form 1571
1.1.2 Application form: FDA form 356(h)
1.1.3 User fee cover sheet: FDA form 3397
1.1.4 Annual report transmittal: FDA form
2252
1.1.5 Advertisements and promotional
labeling transmittal: FDA form 2253
1.1.6 Transmittal of labels & circulars: FDA
form 2567
6
Module 1 TOC
1.2 Cover letters
Submission identification
Submission description
Approximate submission size
Virus free statement
Regulatory & technical point of contact
Module 1 TOC
1.3 Administrative information
1.3.1 Contact/sponsor/applicant information
Module 1 TOC
1.3.5 Patent and exclusivity
1.3.5.1 Patent information
FDA form 3542a
FDA form 3542
1.4 References
1.4.1 Letter of authorization
1.4.2 Statement of right of reference
1.4.3 List of authorized persons to incorporate by
reference
1.4.4 Cross reference to other applications and
previously submitted information
Module 1 TOC
1.5 Application status
Module 1 TOC
1.6 Meetings
1.6.1 Meeting request
1.6.2 Meeting background materials
1.6.3 Correspondence regarding meetings
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
Module 1 TOC
1.12 Other correspondence
Module 1 TOC
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
18
Module 1 TOC
1.14 labeling
1.14.1 Draft labeling
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
20
Module 1 TOC
1.14.4 Investigational drug labeling
1.14.1.1 Investigators brochure
1.14.1.2 Investigational drug Labeling
21
Summary
Module 1 sets the regulatory and legal
framework for applications and
subsequent submissions
Match information to appropriate heading
22
SECTION 1.2
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
esub@cder.fda.gov
esub@cder.fda.gov
eCTD Changes
esub@cder.fda.gov
esub@cder.fda.gov
esub@cder.fda.gov
Submissions 101
esub@cder.fda.gov
Just say no
No paper unless required for original
signatures
No Word files or file formats not
specified in the guidance
No electronic submissions or records
sent directly to a reviewer or project
manager
No electronic desk copies
esub@cder.fda.gov
Just dont do it
Dont send electronic submissions to
the division document rooms
Dont use node extensions in preparing
eCTD
Dont combine multiple documents into
single PDF
Dont send customized style sheets
Dont hide your media place it in the
volume with your cover letter.
esub@cder.fda.gov
References
CDER Contact for information on eCTD
submissions
eSub@cder.fda.gov
esub@cder.fda.gov
SECTION 1.3
esub@cder.fda.gov
Remember!
One of your goals is communication
Clarity improves reviewability
Consider application from reviewers
standpoint
Create document level Tables of Content
with appropriate bookmarks
Use meaningful file names
Use clear concise leaf titles
esub@cder.fda.gov
esub@cder.fda.gov
esub@cder.fda.gov
CDER: ODEVI
All electronic submission to the ODEVI document room
CDER: OGD
All electronic submission to the OGD document room
eCTD
Should not include any paper
If Part 11 compliant electronic signatures are available
otherwise only documents requiring original signatures
Company Name
Drug Name
Submission Type
Submission Date
Application Number
Sequence Number
esub@cder.fda.gov
No Alpha Characters
No - , or other punctuation
No spaces
Six Numbers pad left 0 if 5 digits are given
esub@cder.fda.gov
esub@cder.fda.gov
esub@cder.fda.gov
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
esub@cder.fda.gov
esub@cder.fda.gov
esub@cder.fda.gov
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
esub@cder.fda.gov
esub@cder.fda.gov
References
CDER Contact for information on eCTD
and CTD submissions eSub@cder.fda.gov
Electronic Regulatory Submissions and
Review website
www.fda.gov/cder/regulatory/ersr/default.htm
International Conference on
Harmonization www.ich.org
esub@cder.fda.gov
SECTION 1.4
This section discusses Module 4 and the positions of its various components.
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
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
Analysis datasets
Analysis datasets
Analysis programs
Data definitions
Continuing Education
Questions & Answers (?)
Continuing Education
www.fda.gov
Specifications
Status
Concept paper accepted by steering
committee
Standard operating procedures being
developed
Pilot in 2005
THANK YOU
(301) 827-5583
wilsons@cder.fda.gov
SECTION 1.5
Guidance-Compliant eCTDs:
Module 5
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
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
esub@cder.fda.gov
Study No.
Title
Treatment
Duration
Treated
Location
PK
Studies
AA-001
[Title]
Placebo
1 mg
5 mg
10 mg
1 dose
10
10
10
10
5.3.3.1
AA-002
[Title2]
Placebo
1 mg q d
5 mg q d
2 weeks
10
20
20
5.3.3.1
[Title 3]
Placebo
5 mg qd
1 week
10
15
5.3.4.2
PD
Studies
AB-001
esub@cder.fda.gov
esub@cder.fda.gov
5.3.1
5.3.2
5.3.3
Biopharmaceutics
Human Biomaterials
Human PK Studies
Bioavailability (BA)
Bioequivalence (BE)
Hepatic Metabolism
Healthy Subject /
Patient PK
In-vitro/in-vivo
correlation
Drug Interaction
Intrinsic Factor PK
In-vitro/in-vivo
correlation studies
Extrinsic Factor PK
Bioanalytical/Analytical
Methods for Human
Studies
Bioanalytical/Analytical
Methods for Human
Studies
5.3.4
Human PD
Healthy Subject PD and PK/PD
esub@cder.fda.gov
Population PK
5.3.5
5.3.6
Postmarketing Experience
Uncontrolled studies
Also in 5.3
Case Report Tabulations
Case Report Forms
Use appropriate sections under the specific
study
esub@cder.fda.gov
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
esub@cder.fda.gov
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
esub@cder.fda.gov
FAQ
Q: ISE/ISS: Module 2 or Module 5?
A: Usually Module 5 (section 5.3.5.3) but
can be Module 2 if short. Discuss with
review division.
[remember Module 2 = 50-400 pages]
esub@cder.fda.gov
Summary
Module 5 permits comprehensive
clinical pharmacology, clinical, statistical
reviews
Majority of IND/BLA/NDA clinical
content in section 5.3
A study report now comes in multiple
files (E3) *different from the past*
Datasets and CRFs organized by
study, but still XPT and PDF,
respectively.
esub@cder.fda.gov
SECTION 1.6
eCTDs
Quality/CMC Issues
Norman R. Schmuff, Ph.D.
FDA, CDER
Acting Deputy Division Director
Division of New Drug Chemistry 3
FDA Presentations
June 1992
CANDA Conference
Aster Publishing
New Brunswick, NJ
July 1992
CANDA Conference
IIR
Princeton, NJ
<memo>
DTD
</memo>
XML Memo
<!ELEMENT memo (date, to, from, cc*, topic, sub-topic?, lead-para, body+)>
<!ELEMENT date (#PCDATA)
<!ELEMENT to (#PCDATA)
<!ATTLIST to ID #REQUIRED>
MEMO
Date:
To:
From:
[CC:]
Topic:
[Sub-topic:]
Lead paragraph
Body
Body
+
*
?
one or more
zero or more
zero or one
Quality/CMC Information
Module 1 (Region Specific Information)
Environmental Assessment
Module 2 (Summaries)
2.3 Quality Overall Summary
(Note: only one summary, unlike E & S sections)
Module 3
Drug Substance
Drug Product
Appendices
Regional Information
CTDQ (M4Q)
CTDQ Questions and Answers
eCTD Specification
eCTD Questions and Answers
FDA Documents:
www.fda.gov/cder/guidance
Topics Appearing in
Multiple Sections
A Few Examples
P 2.6 PD Compatibility
One-time compatibility with diluents / devices
P 2.1.2 PD Excipients
Choice, amounts, impact on dp performance
Justification of ranges
P 2.2.2 PD Overages
Dissolution
P 2.1.1 PD Drug Substance
DP manufactured from different particle sizes
Issues to be Resolved
Module 2 Quality Overall Summary
Content
Use
For supplements
Outline
SECTION 1.7
http://www.ich.org
Disclaimer
Views expressed in this presentation
are those of the speaker and not,
necessarily, of the Food and Drug
Administration
Outline
PART I
Background/Motivation
From the ICH CTD
General Guidance on Summaries
ANNEX : Granularity Document
Module 2: Summaries
Mapping from the CFR
PART II
Module 4: Safety
Questions & Answers (?)
Background/Motivation
Regulation, Guidance & Specifications
ICH Common Technical Document
eCTD Review Tools
Guidance
Represents the Agencys current thinking
Not binding on FDA or the public
An alternative approach may be used if
such approach satisfies the requirements of
the applicable statutes, regulations or both.
Guidance does not limit the authority of a
Center and should not supplant
S. Woollen
Regulation
Guidance
Example: Guidance
CTD Introduction
Quality
Overall
Summary
2.3
Nonclinical
Overview
2.4
Nonclinical Written
And Tabulated
Summaries
2.6
Clinical
Overview
2.5
Clinical
l
Summary
i 2.7
Module 2 -- Summaries
Module 2 should contain 7 sections in the
following order :
Module 2: Summaries
2.1 Table of Contents (in XML backbone)
2.2 Introduction to summary
2.3 Quality overall summary
2.4 Non-clinical overview
2.5 Clinical overview
2.6 Non-clinical written and tabulated
summaries
2.7 Clinical summary
Regulation
Guidance
eCTD
312.23(a)(3)(i)
Introductory statement
Introduction to
summary
312.23(a)(3)(iiiv)
Introductory statement
Clinical overall
summary
312.23(a)(8)
Pharmacology and
toxicology information
312.23(a)(8)
Pharmacology and
toxicology information
312.23(a)(9)
Previous human
experience
eCTD
314.50(c)(2)(ii) to
(ix)
Summaries
A.N.
314.50(d)(7)
A.N.
Use appropriate
sections
314.60
Amendments to an
unapproved application
A. N. Use appropriate
sections
A.N.
Use appropriate
sections
314.96
Amendments to an
unapproved application
A.N
Use appropriate
sections
A.N. As Needed
Part 2
Guidances
SECTION 2
TABLE OF CONTENTS
I.
INTRODUCTION .................................................................................................................1
II.
BACKGROUND ....................................................................................................................2
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if that approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
I.
INTRODUCTION
This is one in a series of guidances that provide recommendations for applicants preparing the
Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) for
submission to the U.S. Food and Drug Administration (FDA). This guidance provides answers
to questions that have arisen since the finalization of the harmonized CTD guidance documents
in November 2000. This guidance specifically addresses questions related to efficacy. Other
question and answer (Q &A) guidances are under development to address general questions as
well as questions related to quality and safety. The questions and answers provided here reflect
the consensus of the ICH parties.
This guidance is being revised to include additional questions.
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
1
This guidance was developed within the M4 CTD-Efficacy Implementation Working Group of the International
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document
has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, June 10, 2004. At Step 4 of the
process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the
United States .
II.
BACKGROUND
The guidance for industry issued in November 2000 on preparing the CTD was divided into four
separate documents (1) M4: Organization of the CTD, (2) M4: The CTD Quality, (3) M4:
The CTD Efficacy, and (4) M4: The CTD Safety. Since implementation of these
guidances, a number of questions regarding the various CTD documents have been submitted to
the various ICH regions. The ICH has developed a process for responding to questions
submitted to the ICH Web site.
III.
Q1:
Clinical study reports contained in Module 5 are cited in the Clinical Overview and/or
the Clinical Summary in Module 2. Each clinical study report may be given a unique
short name when cited. Does the method of citing and naming have to be uniform
throughout all modules?
A1:
We recommend that each study have a unique short identifier that is used consistently
throughout the application. The applicant can select the identifier. The full title of the
study is provided in the Tabular Listing of All Clinical Studies (Section 5.2)
Q2:
Definitions/Terminology
What is the definition of Common Adverse Events as used in the CTD?
A2:
Q3:
A3:
How many pages should a Clinical Summary be for an application that contains
multiple indications?
A4:
The estimated size of this document is 50-400 pages, assuming one indication.
Applications that include multiple indications will be larger, reflecting the submission of
multiple efficacy sections.
Q5:
A5:
Section 2.7.3.3 summarizes the data across all studies that characterize efficacy of the
drug; Section 2.7.3.4 provides an integrated summary of the dose-response or blood
concentration-response relationships of effectiveness. In both cases, supportive data from
Section 2.7.2 can also be incorporated.
Q6:
A6:
That table should refer to all subjects exposed to at least one dose of the drug product.
Appropriate subsets of subjects relevant to the proposed indications should also be
identified and considered.
Q7:
A7:
Summaries of any bridging studies using clinical endpoints (i.e., certain studies intended
to evaluate the ability to extrapolate certain types of foreign clinical data to the new
region (see ICH E5)) should be included in Section 2.7.3.2. Where appropriate, such
information should also be described in the summarization of safety data as related to
intrinsic and extrinsic ethnic factors (ICH E5), in Sections 2.7.4.5.1 and 2.7.4.5.2.
Finally, some applications might include in Section 5.3.5.3 a detailed analysis of
bridging, considering formal bridging studies, other relevant clinical studies, and other
A8:
Q9:
A9:
The tabular listing described in section 5.2 is a listing of all clinical studies in the
submission.
An example of such a listing is given in Table 5.1.
Q10
A10:
The ISS/ISE are critical components of the safety and effectiveness submission and are
expected to be submitted in the application in accordance with the regulation. FDAs
guidance Format and Content of Clinical and Statistical Sections of Application gives
advice on how to construct these summaries. Note that, despite the name, these are
integrated analyses of all relevant data, not summaries.
The Clinical Safety sections of the CTD follow approximately the outline of the sections
of the ISS/ISE, although they are somewhat modified by experience with ICH E-3
(Structure and Content of Clinical Study Reports). The CTD Clinical Overview and
Summary in Module 2 will not usually contain the level of detail expected for an ISS. It
may contain the level of detail needed for an ISE, but this would need to be determined
on a case-by-case basis.
If the requirements of 21 CFR 314.50 can be met for a particular application by what is in
the CTD Module 2 summary, the CTD Module 2 section would fulfill the need for an
ISS/ISE. In some cases, it will be convenient to write much of what is needed in the
CTD Module 2 with appropriate appendices in Module 5. In other cases, the ISS/ISE
would be summarized in Module 2, with detailed reports in Module 5.
Any questions about these matters can be raised with the reviewing division.
Q11: Microbiology Data
The microbiology data will include both in vitro and in vivo studies. Where should the
microbiology summary, overview, and study reports be included?
A11:
The microbiology data from both in vitro and in vivo studies should be included with the
Efficacy information. The summary information should be provided in the appropriate
section 2.7 Clinical Summary and the reports should be filed in section 5.3.5.4 Other
Study Reports.
In addition, the microbiology information can be described in the Nonclinical sections as
appropriate.
Since variation is a term from the EU regulations, the answer should be provided by the
EMEA.
Q13: Integrated Analysis of Efficacy (ISE) Section 2.7 Clinical Summary Statistical
Listings
What approach should applicants take for the formatting and presentation of their
integrated analyses when they have large amounts of statistical output to present
(several thousands of pages)?
A13:
As stated in section Reports of Analyses From More Than One Study 5.3.5.3, where the
details of the analysis are too extensive to be reported in a summary document (for
example, section Clinical Summary 2.7), they should be presented in a separate report.
Such report should be placed in section 5.3.5.3.
Providing the section header in addition to the section number improves the clarity of the
reference, particularly for the uninitiated reader. To reduce the length of the cross string
while maintaining the ease of use, it is recommended to include only the section number
in the cross string and write the text so the reader will also know the section content. For
example, as seen in the population PK study 101 (5.3.3.5) helps the reader to find the
referenced study report under the Population PK Study Reports section. The text no
safety problems were noted in the uncontrolled pneumonia study 101A (5.3.5.2) helps
the reader find the referenced study report under the section Study Reports of
Uncontrolled Clinical Studies for the Pneumonia indication.
A fuller discussion of how to describe in the CTD the limitations of the safety database
and the potential implications for the safety of the drug when marketed is as follows:
Nonclinical toxicology and safety pharmacology concerns, such as those arising from
reproductive / developmental toxicity, carcinogenicity, hepatic injury, central nervous
system injury, or effects on cardiac repolarization that are not fully resolved by
available human data, or that arise from incomplete testing.
Identified adverse events and potential adverse events that require further
characterization or evaluation with respect to frequency and/or seriousness in the
general population or in specific subgroups.
Important potential risks (e.g., known risks of pharmacologically related drugs) that
require further evaluation.
Such information should be described and discussed in section 2.5.5 Overview of Safety,
with appropriate cross references to section 2.7.4 Summary of Clinical Safety and any
other relevant sections.
A discussion of any planned postmarketing activity or study to address the limitations of
the premarketing safety database should also be included in section 2.5.5 Overview of
Safety, with any protocols for specific studies provided in section5.3.5.4 Other Clinical
Study Reports or other sections as appropriate (e.g., module 4 if the study is a nonclinical
study).
An ICH guideline (E2E Pharmacovigilance Planning) is being developed to further
address the question of how to describe the safety data and its limitations and how to
describe planned postmarketing activities and studies.
Q16: Multiple Indications
When submitting one dossier for multiple indications, how should the applicant
present them in the clinical part of the registration dossier, for example sections 2.5
Clinical Overview, 2.7.3 Summary of Clinical Efficacy, and 5.3.5 Reports of Efficacy
and Safety Studies?
A16:
Q18: According to ICH E3 Structure and Content of Clinical Study Reports, the case report
forms should be located in Appendix 16.3, the individual patient data listings in
Appendix 16.4, and the publications and literature references in Appendices 16.1.11
and 16.1.12 respectively. The CTD organization provides locations for case report
forms and individual patient data listings in Module 5.3.7 and for literature references
in Module 5.4.
Can clarity be provided as to where these items should actually be placed in CTD and
the eCTD submissions?
A18:
For paper submissions, case report forms and individual patient data listings should be
located in Module 5.3.7, identified by study.
For eCTD, PDF files for case report forms and individual patient data listings should be
organized by study in the folder for Module 5.3.7. However, in the index.xml file, the
leaf elements for the case report forms and individual patient data listings should be
included under the same heading as other study report files with additional information
included with any accompanying study tagging file. In addition, a repeat of the leaf
element can be placed under the heading 5.3.7 Case Report Forms and Individual Patient
Data Listings. Datasets, if required by the region, should be organized according to
regional guidance.
For paper submissions, publications and literature references should be located in Module
5.4.
For eCTD, the files for publications and literature references should be located in the
folder for Module 5.4. However, in the index.xml file, the leaf elements for the
publications and literature references should be included under the same heading as other
study report files with additional information included with any accompanying study
tagging file. In addition, a repeat of the leaf element should be placed under the heading
for 5.4 Literature References.
SECTION 3
The objective of this guideline is to facilitate the compilation of a single core clinical
study report acceptable to all regulatory authorities of the ICH regions. The regulatory
authority-specific additions will consist of modules to be considered as appendices,
available upon request according to regional regulatory requirements.
Table of Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.
TITLE PAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.
SYNOPSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.
4.
5.
ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) . . . . .
5.2
Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3
Patient Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.
7.
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
8.
STUDY OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
9.
INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
9.1
Overall Study Design and Plan: Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
9.2
Discussion of Study Design, Including the Choice of Control Groups . . . . . . . . . 7
9.3
Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.3.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.3.2 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.3.3 Removal of Patients From Therapy or Assessment . . . . . . . . . . . . . . . . . 9
9.4
Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.4.1 Treatments Administered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
9.4.2 Identity of Investigational Products(s) . . . . . . . . . . . . . . . . . . . . . . . . . . 10
9.4.3 Method of Assigning Patients to Treatment Groups . . . . . . . . . . . . . . . 10
9.4.4 Selection of Doses in the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
9.4.5 Selection and Timing of Dose for Each Patient . . . . . . . . . . . . . . . . . . . 11
9.4.6 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
9.4.7 Prior and Concomitant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
9.4.8 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
9.5
Efficacy and Safety Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart . . . . . . . . . 12
9.5.2 Appropriateness of Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
9.5.3 Primary Efficacy Variable(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
i
...5
................. 5
5
5
5
5
............ 5
9.6
9.7
9.8
14
14
15
15
15
16
10.
STUDY PATIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
10.1 Disposition of Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
10.2 Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
11.
EFFICACY EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1 Data Sets Analyzed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2 Demographic and Other Baseline Characteristics . . . . . . . . . . . . . . . . . . . . . . .
11.3. Measurements of Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4 Efficacy Results and Tabulations of Individual Patient Data . . . . . . . . . . . . . . .
11.4.1 Analysis of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4.2 Statistical/Analytical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4.2.1
Adjustments for Covariates . . . . . . . . . . . . . . . . . . . . . .
11.4.2.2
Handling of Dropouts or Missing Data . . . . . . . . . . . . . .
11.4.2.3
Interim Analyses and Data Monitoring . . . . . . . . . . . . . .
11.4.2.4
Multicenter Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4.2.5
Multiple Comparisons/Multiplicity . . . . . . . . . . . . . . . . .
11.4.2.6
Use of an Efficacy Subset of Patients . . . . . . . . . . . . .
11.4.2.7
Active-Control Studies Intended to Show Equivalence . .
11.4.2.8
Examination of Subgroups . . . . . . . . . . . . . . . . . . . . . . .
11.4.3 Tabulation of Individual Response Data . . . . . . . . . . . . . . . . . . . . . . . .
11.4.4 Drug Dose, Drug Concentration, and Relationships to Response . . . . . .
11.4.5 Drug-Drug and Drug-Disease Interactions . . . . . . . . . . . . . . . . . . . . . .
11.4.6 By-Patient Displays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4.7 Efficacy Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
17
18
19
19
19
20
20
21
21
22
22
22
23
23
23
24
25
25
25
12.
SAFETY EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.1 Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2.1 Brief Summary of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2.2 Display of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2.3 Analysis of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2.4 Listing of Adverse Events by Patient . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.3. Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
.
12.3.1 Listing of Deaths, Other Serious Adverse Events, and Other Significant
Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.3.1.1
Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
26
27
27
27
29
29
30
ii
30
31
12.4
12.5.
12.6
12.3.1.2
Other Serious Adverse Events . . . . . . . . . . . . . . . . . . . .
12.3.1.3
Other Significant Adverse Events . . . . . . . . . . . . . . . . . .
12.3.2 Narratives of Deaths, Other Serious Adverse Events, and Certain Other
Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse Events, and
Other Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.4.1 Listing of Individual Laboratory Measurements by Patient (Appendix
16.2.8) and Each Abnormal Laboratory Value (see section 14.3.4) . . . .
12.4.2 Evaluation of Each Laboratory Parameter . . . . . . . . . . . . . . . . . . . . . . .
12.4.2.1
Laboratory Values Over Time . . . . . . . . . . . . . . . . . . . .
12.4.2.2
Individual Patient Changes . . . . . . . . . . . . . . . . . . . . . . .
12.4.2.3.
Individual Clinically Significant Abnormalities . . . . . . . .
Vital Signs, Physical Findings, and Other Observations Related to Safety . . . . .
Safety Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
31
31
32
32
32
33
33
34
34
35
35
13.
14.
15.
REFERENCE LIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
16.
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1 Study Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.1 Protocol and protocol amendments. . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.2 Sample case report form (unique pages only).
. . . . . . . . . . . . . . . . . . . 37
16.1.3 List of IEC's or IRB's (plus the name of the committee chair if required by
the regulatory authority) and representative written information for patient
and sample consent forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.4 List and description of investigators and other important participants in the
study, including brief (one page) CV's or equivalent summaries of training
and experience relevant to the performance of the clinical study.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
16.1.5 Signatures of principal or coordinating investigator(s) or sponsor's
iii
. . . . . . . . . . . . . . . . . . . . . . . . . . . 35
16.2
16.3.
16.4
SYNOPSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Annex I
. . . . . . . . Annex IIIa
. . . . . . . . Annex IIIb
iv
. . . . . . . Annex V
Annex VII
The guideline is intended to assist sponsors in the development of a report that is complete, free
from ambiguity, well organized, and easy to review. The report should provide a clear explanation
1
This guideline was developed within the Expert Working Group (Efficacy) of the International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed
by the ICH Steering Committee at Step 4 of the ICH process, November 29, 1995. At Step 4 of the process, the final
draft is recommended for adoption to the regulatory bodies of the European Union, Japan and the USA. This guideline
was published in the Federal Register on July 17, 1996 (61 FR 37320) and is applicable to drug and biological
products. Although this guideline does not create or confer any rights for or on any person and does not operate to bind
FDA or the industry, it does represent the Agencys current thinking on structure and content of clincial study reports.
For additional copies of this guideline, contact the Drug Information Branch, HFD-210, CDER, FDA, 5600 Fishers
Lane, Rockville, MD 20857 (Phone: 301-827-4573) or the Manufacturers Assistance and Communication Staff (HFM42), CBER, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed adhesive label to assist
the offices in processing your request. An electronic version of this guidance is also available via Internet using the
World Wide Web (WWW) (connect to the CDER Home Page at WWW.FDA.GOV/CDER and go to the Regulatory
Guidance section).
of how the critical design features of the study were chosen and enough information on the plan,
methods, and conduct of the study so that there is no ambiguity in how the study was carried out.
The report with its appendices should also provide enough individual patient data, including the
demographic and baseline data, and details of analytical methods, to allow replication of the
critical analyses when authorities wish to do so. It is also particularly important that all analyses,
tables, and figures carry, in text or as part of the table, clear identification of the set of patients
from which they were generated.
Depending on the regulatory authority's review policy, abbreviated reports using summarized data
or with some sections deleted may be acceptable for uncontrolled studies or other studies not
designed to establish efficacy, for seriously flawed or aborted studies, or for controlled studies
that examine conditions clearly unrelated to those for which a claim is made. A controlled safety
study, however, should be reported in full. If an abbreviated report is provided, a full description
of safety aspects should be included in all cases. If an abbreviated report is submitted, there should
be enough detail of design and results to allow the regulatory authority to determine whether a
full report is needed. If there is any question regarding whether the reports are needed, it may be
useful to consult the regulatory authority.
In presenting the detailed description of how the study was carried out, it may be possible simply
to restate the description in the initial protocol. Often, however, it is possible to present the
methodology of the study more concisely in a separate document. In each section describing the
design and conduct of the study, it is particularly important to clarify features of the study that are
not well-described in the protocol and identify ways in which the study as conducted differed from
the protocol, and to discuss the statistical methods and analyses used to account for these
deviations from the planned protocol.
The full integrated report of the individual study should include the most detailed discussion of
individual adverse events or laboratory abnormalities, but these should usually be reexamined as
part of an overall safety analysis of all available data in any application.
The report should describe demographic and other potentially predictive characteristics of the
study population and, where the study is large enough to permit this, present data for
demographic (e.g., age, sex, race, weight) and other (e.g., renal or hepatic function) subgroups so
that possible differences in efficacy or safety can be identified. Usually, however, subgroup
responses should be examined in the larger data base used in the overall analysis.
The data listings requested as part of the report (usually in an appendix) are those needed to
support critical analyses. Data listings that are part of the report should be readily usable by the
reviewer. Thus, although it may be desirable to include many variables in a single listing to limit
size, this should not be at the expense of clarity. An excess of data should not be allowed to lead
to, for example, overuse of symbols instead of words or easily understood abbreviations, or to
too-small displays. In this case, it is preferable to produce several listings.
Data should be presented in the report at different levels of detail: Overall summary figures and
tables for important demographic, efficacy, and safety variables may be placed in the text to
illustrate important points; other summary figures, tables, and listings for demographic, efficacy,
and safety variables should be provided in section 14; individual patient data for specified groups
of patients should be provided as listings in Appendix 16.2; and all individual patient data
(archival listings requested only in the United States) should be provided in Appendix 16.4.
In any table, figure, or data listing, estimated or derived values, if used, should be identified in a
conspicuous fashion. Detailed explanations should be provided as to how such values were
estimated or derived and what underlying assumptions were made.
The guidance provided below is detailed and is intended to notify the applicant of virtually all of
the information that should routinely be provided so that postsubmission requests for further data
clarification and analyses can be reduced as much as possible. Nonetheless, specific requirements
for data presentation and/or analysis may depend on specific situations, may evolve over time,
may vary from drug class to drug class, may differ among regions, and cannot be described in
general terms. It is, therefore, important to refer to specific clinical guidelines and to discuss data
presentation and analyses with the reviewing authority, whenever possible. Detailed written
guidance on statistical approaches is available from some authorities.
Each report should consider all of the topics described (unless clearly not relevant) although the
specific sequence and grouping of topics may be changed if alternatives are more logical for a
particular study. Some data in the appendices are specific requirements of individual regulatory
authorities and should be submitted as appropriate. The numbering should then be adapted
accordingly.
In the case of very large trials, some of the provisions of this guideline may be impractical or
inappropriate. When planning and when reporting such trials, contact with regulatory authorities
to discuss an appropriate report format is encouraged.
The provisions of this guideline should be used in conjunction with other ICH guidelines.
1.
TITLE PAGE
SYNOPSIS
A brief synopsis (usually limited to three pages) that summarizes the study should be provided
(see Annex I of the guideline for an example of a synopsis format used in Europe). The synopsis
should include numerical data to illustrate results, not just text or p-values.
3.
TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY
REPORT
The table of contents should include:
The page number or other locating information of each section, including summary tables,
figures, and graphs.
A list and the locations of appendices, tabulations, and any case report forms provided.
4.
A list of the abbreviations, and lists and definitions of specialized or unusual terms or
measurement units used in the report should be provided. Abbreviated terms should be spelled out
and the abbreviation indicated in parentheses at first appearance in the text.
5.
ETHICS
5.1
It should be confirmed that the study and any amendments were reviewed by an IEC or
IRB. A list of all IEC's or IRB's consulted should be given in Appendix 16.1.3 and, if
required by the regulatory authority, thename of the committee Chair should be provided.
5.2
It should be confirmed that the study was conducted in accordance with the ethical
principles that have their origins in the Declaration of Helsinki.
5.3
How and when informed consent was obtained in relation to patient enrollment (e.g., at
allocation, prescreening) should be described.
Representative written information for the patient (if any) and a sample of the patient
consent form used should be provided in Appendix 16.1.3.
6.
The administrative structure of the study (e.g., principal investigator, coordinating investigator,
steering committee, administration, monitoring and evaluation committees, institutions,
statistician, central laboratory facilities, contract research organization (C.R.O.), clinical trial
supply management) should be described briefly in the body of the report.
There should be provided in Appendix 16.1.4 a list of the investigators with their affiliations, their
role in the study, and their qualifications (curriculum vitae or equivalent). A similar list for other
persons whose participation materially affected the conduct of the study should also be provided
in Appendix 16.1.4. In the case of large trials with many investigators, the above information may
5
be abbreviated to consist of general statements of qualifications for persons carrying out particular
roles in the study with only the name, degree, and institutional affiliation and roles of each
investigator or other participant.
The listing should include:
A.
Investigators.
B.
Any other person carrying out observations of primary or other major efficacy
variables, such as a nurse, physician's assistant, clinical psychologist, clinical pharmacist,
or house staff physician. It is not necessary to include in this list a person with only an
occasional role, e.g., an on-call physician who dealt with a possible adverse effect or a
temporary substitute for any of the above.
C.
INTRODUCTION
The introduction should contain a brief statement (maximum: one page) placing the study in the
context of the development of the test drug/investigational product, relating the critical features of
the study (e.g., rationale and aims, target population, treatment, duration, primary endpoints) to
that development. Any guidelines that were followed in the development of the protocol or any
other agreements/meetings between the sponsor/company and regulatory authorities that are
relevant to the particular study should be identified or described.
8.
STUDY OBJECTIVES
9.
INVESTIGATIONAL PLAN
9.1
The overall study plan and design (configuration) of the study (e.g., parallel, cross-over)
should be described briefly but clearly, using charts and diagrams as needed. If other
6
studies used a very similar protocol, it may be useful to note this and describe any
important differences. The actual protocol and any changes should be included as
Appendix 16.1.1 and a sample case report form (unique pages only; i.e., it is not necessary
to include identical pages from forms for different evaluations or visits) as Appendix
16.1.2. If any of the information in this section comes from sources other than the
protocol, these should be identified.
The information provided should include:
Treatments studied (specific drugs, doses, and procedures).
Patient population studied and the number of patients to be included.
Level and method of blinding/masking (e.g., open, double-blind, single-blind,
blinded evaluators, and unblinded patients and/or investigators).
Kind of control(s) (e.g., placebo, no treatment, active drug, dose-response,
historical) and study configuration (parallel, cross-over).
Method of assignment to treatment (randomization, stratification).
Sequence and duration of all study periods, including prerandomization and
post-treatment periods, therapy withdrawal periods, and single and double-blind
treatment periods. When patients were randomized should be specified. It is
usually helpful to display the design graphically with a flow chart that includes
timing of assessments (see Annexes IIIa and IIIb for an example).
Any safety, data monitoring, or special steering or evaluation committees.
Any interim analyses.
9.2
The specific control chosen and the study design used should be discussed, as necessary.
Examples of design issues meriting discussion follow.
Generally, the control (comparison) groups that are recognized are placebo concurrent
control, no treatment concurrent control, active treatment concurrent control, dose
comparison concurrent control, and historical control. In addition to the type of control,
other critical design features that may need discussion are use of a cross-over design and
selection of patients with particular prior history, such as response or nonresponse to a
specific drug or member of a drug class. If randomization was not used, it is important to
explain how other techniques, if any, guarded against systematic selection bias.
7
Known or potential problems associated with the study design or control group chosen
should be discussed in light of the specific disease and therapies being studied. For a
cross-over design, for example, there should be consideration, among other things, of the
likelihood of spontaneous change in the disease and of carry-over effects of treatment
during the study.
If efficacy was to be demonstrated by showing equivalence, i.e., the absence of a specified
degree of inferiority of the new treatment compared to an established treatment, problems
associated with such study designs should be addressed. Specifically, there should be
provided a basis for considering the study capable of distinguishing active from inactive
therapy. Support may be provided by an analysis of previous studies similar to the present
study with respect to important design characteristics (e.g., patient selection, study
endpoints, duration, dose of active control, concomitant therapy) showing a consistent
ability to demonstrate superiority of the active control to placebo. How to assess the
ability of the present study to distinguish effective from ineffective therapy should also be
discussed. For example, it may be possible to identify a treatment response (based on past
studies) that would clearly distinguish between the treated population and an untreated
group. Such a response could be the change of a measure from baseline or some other
specified outcome like healing rate or survival rate. Attainment of such a response would
support the expectation that the study could have distinguished the active drug from an
inactive drug. There should also be a discussion of the degree of inferiority of the therapy
(often referred to as the delta value) the study was intended to show was not exceeded.
The limitations of historical controls are well known (e.g., difficulty of assuring
comparability of treated groups, inability to blind investigators to treatment, change in
therapy/disease, difference due to placebo effect) and deserve particular attention.
Other specific features of the design may also deserve discussion, including presence or
absence of washout periods and the duration of the treatment period, especially for a
chronic illness. The rationale for dose and dose-interval selection should be explained, if it
is not obvious. For example, once daily dosing with a short half-life drug whose effect is
closely related in time to blood level is not usually effective; if the study design uses such
dosing, this should be explained, e.g., by pointing to pharmacodynamic evidence that
effect is prolonged compared to blood levels. The procedures used to seek evidence of
escape from drug effect at the end of the dose-interval, such as measurements of effect
just before dosing, should be described. Similarly, in a parallel design dose-response study,
the choice of doses should be explained.
9.3
Inclusion Criteria
The patient population and the selection criteria used to enter the patients into the
8
study should be described, and the suitability of the population for the purposes of
the study discussed. Specific diagnostic criteria used, as well as specific
disease(e.g., disease of a particular severity or duration, results of a particular test
or rating scale(s) or physical examination, particular features of clinical history,
such as failure or success on prior therapy, or other potential prognostic factors
and any age, sex, or ethnic factors) should be presented.
Screening criteria and any additional criteria for randomization or entry into the
test drug/investigational product treatment part of the trial should be described. If
there is reason to believe that there were additional entry criteria, not defined in the
protocol, the implications of these should be discussed. For example, some
investigators may have excluded or entered into other studies patients who were
particularly ill or who had particular baseline characteristics.
9.3.2
Exclusion Criteria
The criteria for exclusion at entry into the study should be specified and the
rationale provided (e.g., safety concerns, administrative reasons, or lack of
suitability for the trial). The impact of exclusions on the generalizability of the
study should be discussed in section 13 of the study report or in an overview of
safety and efficacy.
9.3.3
Treatments
9.4.1
Treatments Administered
The specific methods used to assign patients to treatment groups, e.g., centralized
allocation, allocation within sites, adaptive allocation (that is, assignment on the
basis of earlier assignment or outcome) should be described in the text of the
report, including any stratification or blocking procedures. Any unusual features
should be explained.
A detailed description of the randomization method, including how it was
executed, should be given in Appendix 16.1.7 with references cited if necessary. A
table exhibiting the randomization codes, patient identifier, and treatment assigned
should also be presented in the Appendix. For a multicenter study, the information
should be given by center. The method of generating random numbers should be
explained.
For a historically controlled trial, it is important to explain how the particul ar
control was selected and what other historical experiences were examined, if any,
and how their results compared to the control used.
9.4.4
The doses or dose ranges used in the study should be given for all treatments and
the basis for choosing them described (e.g., prior experience in humans, animal
data).
9.4.5
Procedures for selecting each patient's dose of test drug/ investigational product
and active control/comparator should be described. These procedures can vary
from simple random assignment to a selected fixed drug/dose regimen, to use of a
specified titration procedure, or to more elaborate response-determined selection
procedures, e.g., where dose is titrated upward at intervals until intolerance or
10
Blinding
Which drugs or procedures were allowed before and during the study, whether and
11
how their use was recorded, and any other specific rules and procedures related to
permitted or prohibited concomitant therapy should be described. How allowed
concomitant therapy might affect the outcome due either to drug-drug interaction
or to direct effects on the study endpoints should be discussed, and how the
independent effects of concomitant and study therapies could be ascertained
should be explained.
9.4.8
Treatment Compliance
The specific efficacy and safety variables to be assessed and laboratory tests to be
conducted, their schedule (days of study, time of day, relation to meals, and the
timing of critical measures in relation to test drug administration, e.g., just prior to
next dose, 2 hours after dose), the methods for measuring them, and the persons
responsible for the measurements should be described. If there were changes in
personnel carrying out critical measurements, these should be reported.
It is usually helpful to display graphically in a flow chart (see Annex III of the
guideline) the frequency and timing of efficacy and safety measurements; visit
numbers and times should be shown, or, alternatively, times alone can be used
(visit numbers alone are more difficult to interpret). Any specific instructions (e.g.,
guidance or use of a diary) to the patients should also be noted.
Any definitions used to characterize outcome (e.g., criteria for determining
occurrence of acute myocardial infarction, designation of the location of the
infarction, characterization of a stroke as thrombotic or hemorrhagic, distinction
between TIA and stroke, assignment of cause of death) should be explained in full.
Any techniques used to standardize or compare results of laboratory tests or other
clinical measurements (e.g., ECG, chest X-ray) should also be described. This is
particularly important in multicenter studies.
If anyone other than the investigator was responsible for evaluation of clinical
outcomes (e.g., the sponsor or an external committee to review X-rays or ECG's
or to determine whether the patient had a stroke, acute infarction, or sudden
death), the person or group should be identified. The procedures used, including
means of maintaining blindness and centralizing readings and measurements,
12
Appropriateness of Measurements
If any of the efficacy or safety assessments was not standard, i.e., widely used and
generally recognized as reliable, accurate, and relevant (able to discriminate
between effective and ineffective agents), its reliability, accuracy, and relevance
should be documented. It may be helpful to describe alternatives considered but
rejected.
If a surrogate endpoint (a laboratory measurement or physical measurement or sign
that is not a direct measure of clinical benefit) was used as a study endpoint, this
should be justified, e.g., by reference to clinical data, publications, guidelines, or
previous actions by regulatory authorities.
9.5.3
13
9.5.4
Any drug concentrations to be measured and the sample collection times and
periods in relation to the timing of drug administration should be described. Any
relation of drug administration and sampling to ingestion of food, posture, and the
possible effects of concomitant medication/alcohol/ caffeine/nicotine should also be
addressed. The biological sample measured, the handling of samples and the
method of measurement used should be described, referring to published and/or
internal assay validation documentation for methodological details. Where other
factors are believed important in assessing pharmacokinetics (e.g., soluble
circulating receptors, renal or hepatic function), the timing and plans to measure
these factors should also be specified.
9.6
The quality assurance and quality control systems implemented to assure the quality of the
data should be described in brief. If none were used, this should be stated. Documentation
of inter-laboratory standardization methods and quality assurance procedures, if used,
should be provided under Appendix 16.1.10.
Any steps taken at the investigation site or centrally to ensure the use of standard
terminology and the collection of accurate, consistent, complete, and reliable data, such as
training sessions, monitoring of investigators by sponsor personnel, instruction manuals,
data verification, cross-checking, use of a central laboratory for certain tests, centralized
ECG reading, or data audits, should be described. It should be noted whether investigator
meetings or other steps were taken to prepare investigators and standardize performance.
If the sponsor used an independent internal or external auditing procedure, it should be
mentioned here and described in Appendix 16.1.8; audit certificates, if available, should be
provided in the same appendix.
9.7
Size
The statistical analyses planned in the protocol and any changes made before
outcome results were available should be described. In this section, emphasis
should be on which analyses, comparisons, and statistical tests were planned, not
on which ones were actually used. If critical measurements were made more than
once, the particular measurements (e.g., average of several measurements over the
entire study, values at particular times, values only from study completers, or last
on-therapy value) planned as the basis for comparison of test drug/investigational
product and control should be specified. Similarly, if more than one analytical
14
The planned sample size and the basis for it, such as statistical considerations or
practical limitations, should be provided. Methods for sample size calculation
should be given together with their derivations or source of reference. Estimates
used in the calculations should be given, and explanations should be provided as to
how they were obtained. For a study intended to show a difference between
treatments, the difference the study is designed to detect should be specified. For a
positive control study intended to show that a new therapy is at least as effective
as the standard therapy, the sample size determination should specify the difference
between treatments that would be considered unacceptably large and, therefore,
the difference the study is designed to be able to exclude.
9.8
Any change in the conduct of the study or planned analyses (e.g., dropping a treatment
group, changing the entry criteria or drug dosages, adjusting the sample size) instituted
after the start of the study should be described. The time(s) and reason(s) for the
change(s), the procedure used to decide on the change(s), the person(s) or group(s)
responsible for the change(s) and the nature and content of the data available (and to
whom they were available) when the change was made should also be described, whether
the change was documented as a formal protocol amendment or not. Personnel changes
need not be included. Any possible implications of the change(s) for the interpretation of
the study should be discussed briefly in this section and more fully in other appropriate
sections of the report. In every section of the report, a clear distinction between conditions
15
STUDY PATIENTS
10.1
Disposition of Patients
There should be a clear accounting of all patients who entered the study, using figures or
tables in the text of the report. The numbers of patients who were randomized and who
entered and completed each phase of the study (or each week/month of the study) should
be provided, as well as the reasons for all postrandomization discontinuations, grouped by
treatment and by major reason (e.g., lost to followup, adverse event, poor compliance). It
may also be relevant to provide the number of patients screened for inclusion and a
breakdown of the reasons for excluding patients during screening, if this could help clarify
the appropriate patient population for eventual drug use. A flow chart is often helpful (see
Annexes IVa and IVb for examples). Whether patients are followed for the duration of the
study, even if drug is discontinued, should be made clear.
In Appendix 16.2.1, there should also be a listing of all patients discontinued from the
study after enrollment, broken down by center and treatment group, giving a patient
identifier, the specific reason for discontinuation, the treatment (drug and dose),
cumulative dose (where appropriate), and the duration of treatment before
discontinuation. Whether or not the blind for the patient was broken at the time of
discontinuation should be noted. It may also be useful to include other information, such
as critical demographic data (e.g., age, sex, race), concomitant medication, and the major
response variable(s) at termination. See Annex V for an example of such a listing.
10.2
Protocol Deviations
All important deviations related to study inclusion or exclusion criteria, conduct of the
trial, patient managements or patient assessment should be described.
In the body of the text, protocol deviations should be appropriately summarized by center
and grouped into different categories, such as:
Those who entered the study even though they did not satisfy the entry criteria.
Those who developed withdrawal criteria during the study but were not
withdrawn.
Those who received the wrong treatment or incorrect dose.
16
EFFICACY EVALUATION
11.1
Exactly which patients were included in each efficacy analysis should be precisely defined,
e.g., all patients receiving any test drugs/investigational products, all patients with any
efficacy observation or with a certain minimum number of observations, only patients
completing the trial, all patients with an observation during a particular time window, or
only patients with a specified degree of compliance. It should be clear, if not defined in the
study protocol, when (relative to study unblinding) and how inclusion/exclusion criteria
for the data sets analyzed were developed. Generally, even if the applicant's proposed
primary analysis is based on a reduced subset of the patients with data, there should also
be, for any trial intended to establish efficacy, an additional analysis using all randomized
(or otherwise entered) patients with any on-treatment data.
There should be a tabular listing of all patients, visits, and observations excluded from the
efficacy analysis provided in Appendix 16.2.3 (see Annex VI for an example). The reasons
for exclusions should also be analyzed for the whole treatment group over time (see
Annex VII for an example).
11.2
Group data for the critical demographic and baseline characteristics of the patients, as well
as other factors arising during the study that could affect response, should be presented in
this section and comparability of the treatment groups for all relevant characteristics
should be displayed by use of tables or graphs in section 14.1. The data for the patient
sample included in the all patients with data analysis should be given first. This may be
followed by data on other groups used in principal analyses, such as the per-protocol
analysis or other analyses, e.g., groups defined by compliance, concomitant
disease/therapy, or demographic/baseline characteristics. When such groups are used, data
for the complementary excluded group should also be shown. In a multicenter study,
where appropriate, comparability should be assessed by center, and centers should be
compared.
A diagram showing the relationship between the entire sample and any other analysis
groups should be provided.
The critical variables will depend on the specific nature of the disease and on the protocol
17
Any measurements of compliance of individual patients with the treatment regimen under
study and drug concentrations in body fluids should be summarized, analyzed by treatment
group and time interval, and tabulated in Appendix 16.2.5.
11.4
18
11.4.2.2
There are several factors that may affect dropout rates. These include the
duration of the study, the nature of the disease, the efficacy and toxicity of
the drug under study, and other factors that are not therapy-related.
Ignoring the patients who dropped out of the study and drawing
conclusions based only on patients who completed the study can be
misleading. A large number of dropouts, however, even if included in an
analysis, may introduce bias, particularly if there are more early dropouts in
one treatment group or the reasons for dropping out are treatment or
outcome related. Although the effects of early dropouts, and sometimes
even the direction of bias, can be difficult to determine, possible effects
should be explored as fully as possible. It may be helpful to examine the
observed cases at various times or, if dropouts were very frequent, to
concentrate on analyses at times when most of the patients were still under
observation and when the full effect of the drug was realized. It may also
be helpful to examine modeling approaches to the evaluation of such
incomplete data sets.
The results of a clinical trial should be assessed not only for the subset of
patients who completed the study, but also for the entire patient population
as randomized or at least for all those with any on-study measurements.
20
Multicenter Studies
11.4.2.5
Multiple Comparisons/Multiplicity
Examination of Subgroups
SAFETY EVALUATION
Analysis of safety-related data can be considered at three levels. First, the extent of exposure
(dose, duration, number of patients) should be examined to determine the degree to which safety
can be assessed from the study. Second, the more common adverse events and laboratory test
changes should be identified, classified in some reasonable way, compared for treatment groups,
and analyzed, as appropriate, for factors that may affect the frequency of adverse reactions/events,
such as time dependence, relation to demographic characteristics, relation to dose or drug
concentration. Finally, serious adverse events and other significant adverse events should be
identified, usually by close examination of patients who left the study prematurely because of an
adverse event, whether or not identified as drug related, or who died.
The ICH Guideline entitled Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting defines serious adverse events as follows: A serious adverse event
(experience) or reaction is any untoward medical occurrence that at any dose: results in death, is
life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization,
results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
For the purpose of this guideline, other significant adverse events are marked hematological and
other laboratory abnormalities and any adverse events that led to an intervention, including
withdrawal of drug treatment, dose reduction, or significant additional concomitant therapy.
In the following sections, three kinds of analysis and display are called for:
1.
Summarized data, often using tables and graphical presentations presented in the main
body of the report;
2.
Listings of individual patient data; and
3.
Narrative statements of events of particular interest.
In all tabulations and analyses, events associated with both test drug and control treatment should
be displayed.
12.1
Extent of Exposure
The extent of exposure to test drugs/investigational products (and to active control and
placebo) should be characterized according to the number of patients exposed, the
duration of exposure, and the dose to which they were exposed.
Duration: Duration of exposure to any dose can be expressed as a median or
mean, but it is also helpful to describe the number of patients exposed for specified
periods of time, such as for 1 day or less, 2 days to 1 week, more than 1 week to 1
25
Adverse Events
12.2.1 Brief Summary of Adverse Events
The overall adverse event experience in the study should be described in a brief
narrative, supported by the following more detailed tabulations and analyses. In
these tabulations and analyses, events associated with both the test drug and
control treatment should be displayed.
12.2.2 Display of Adverse Events
All adverse events occurring after initiation of study treatments (including events
likely to be related to the underlying disease or likely to represent concomitant
illness, unless there is a prior agreement with the regulatory authority to consider
specified events as disease related) should be displayed in summary tables (section
14.3.1). The tables should include changes in vital signs and any laboratory
changes that were considered serious adverse events or other significant adverse
events.
26
In most cases, it will also be useful to identify in such tables treatment emergent
signs and symptoms (TESS: events not seen at baseline and events that worsened
even if present at baseline).
The tables should list each adverse event, the number of patients in each treatment
group in whom the event occurred, and the rate of occurrence. When treatments
are cyclical, e.g., cancer chemotherapy, it may also be helpful to list results
separately for each cycle. Adverse events should be grouped by body system. Each
event may then be divided into defined severity categories (e.g., mild, moderate,
severe) if these were used. The tables may also divide the adverse events into those
considered at least possibly related to drug use and those considered not related,
or use another causality scheme (e.g., unrelated or possibly, probably, or definitely
related). Even when such a causality assessment is used, the tables should include
all adverse events, whether or not considered drug related, including events
thought to represent intercurrent illnesses. Subsequent analyses of the study or of
the overall safety data base may help to distinguish between adverse events that
are, or are not, considered drug related. So that it is possible to analyze and
evaluate the data in these tables, it is important to identify each patient having each
adverse event. An example of such a tabular presentation is shown below.
ADVERSE EVENTS: NUMBER OBSERVED AND RATE,
WITH PATIENT IDENTIFICATION
Treatment Group X
Mild
Related 1
N=50
Moderate
NR 1
Related
NR
Severe
Related
Total
Total
NR
Related
NR
12(24%)
4(8%)
Body
System A
Event 1
6(12%)
2(4%)
3(6%)
1(2%)
3(6%)
1(2%)
N11 2
N21
N31
N41
N51
N61
N12
N22
N32
N52
N33
N53
N13
N14
N15
N16
Event 2
27
R+NR
1
2
should be listed in Appendix 16.2.7, giving both preferred term and the original
term used by the investigator. The listing should be by investigator and by
treatment group and should include:
Patient identifier.
Age, race, sex, weight (height, if relevant).
Location of case report forms, if provided.
The adverse event (preferred term, reported term).
Duration of the adverse event.
Severity (e.g., mild, moderate, severe).
Seriousness (serious/nonserious).
Action taken (none, dose reduced, treatment stopped, specific treatment
instituted, and so forth).
Outcome (e.g., CIOMS format).
Causality assessment (e.g., related/not related). How this was determined
should be described in the table or elsewhere.
Date of onset or date of clinic visit at which the event was discovered.
Timing of onset of the adverse event in relation to the last dose of the test
drug/investigational product (when applicable).
Study treatment at the time of event or the most recent study treatment
taken.
Test drug/investigational product dose in absolute amount, mg/kg or
mg/m<SUP>2, at time of event.
Drug concentration (if known).
Duration of test drug/investigational product treatment.
Concomitant treatment during study.
29
Any abbreviations and codes should be clearly explained at the beginning of the
listing or, preferably, on each page.
12.3.
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
Deaths, other serious adverse events, and other significant adverse events deserve special
attention.
12.3.1 Listing of Deaths, Other Serious Adverse Events, and Other Significant
Adverse Events
Listings, containing the same information as called for in section 12.2.4, should be
provided for the following events.
12.3.1.1
Deaths
All deaths during the study, including the post-treatment followup period,
and deaths that resulted from a process that began during the study, should
be listed by patient in section 14.3.2.
12.3.1.2
All serious adverse events (other than death but including the serious
adverse events temporally associated with or preceding the deaths) should
be listed in section 14.3.2. The listing should include laboratory
abnormalities, abnormal vital signs, and abnormal physical observations
that were considered serious adverse events.
12.3.1.3
31
Time
Age
#1
T0
70
#2
Weight
Dose
SGOT
SGPT
AP
70 kg
400 mg
V1
V5
V9
T1
V2
V6
V10
T2
V3
V7
V11
T3
V4
V8
V12
V13
V16
V19
T21
V14
V17
V20
T32
V15
V18
V21
T10
65
Sex
Race
50 kg
300 mg
For all regulatory authorities, there should be a by-patient listing of all abnormal
laboratory values in section 14.3.4, using the format described above. For
laboratory abnormalities of special interest (abnormal laboratory values of potential
clinical importance), it may also be useful to provide additional data, such as
normal values before and after the abnormal value, and values of related laboratory
tests. In some cases, it may be desirable to exclude certain abnormal values from
further analysis. For example, single, nonreplicated, small abnormalities of some
tests (e.g., uric acid or electrolytes) or occasional low values of some tests (e.g.,
transaminase, alkaline phosphatase, or BUN) can probably be defined as clinically
insignificant and excluded. Any such decisions should be clearly explained,
however, and the complete list of values provided (or available to authorities on
request) should identify every abnormal value.
12.4.2 Evaluation of Each Laboratory Parameter
32
For each parameter at each time over the course of the study (e.g., at each
visit) the following should be described: The group mean or median values,
the range of values, and the number of patients with abnormal values or
with abnormal values that are of a certain size (e.g., twice the upper limit of
normal or five times the upper limit; choices should be explained). Graphs
may be used.
12.4.2.2
Vital signs, other physical findings, and other observations related to safety should be
analyzed and presented in a way similar to laboratory variables. If there is evidence of a
drug effect, any dose-response or drug-concentration-response relationship or relationship
to patient variables (e.g., disease, demographics, concomitant therapy) should be identified
and the clinical relevance of the observation described. Particular attention should be given
to changes not evaluated as efficacy variables and to those considered to be adverse
events.
12.6
Safety Conclusions
The efficacy and safety results of the study and the relationship of risks and benefits should be
briefly summarized and discussed, referring to the tables, figures, and sections above as needed.
The presentation should not simply repeat the description of results nor introduce new results.
The discussion and conclusions should clearly identify any new or unexpected findings, comment
on their significance, and discuss any potential problems such as inconsistencies between related
measures. The clinical relevance and importance of the results should also be discussed in the light
of other existing data. Any specific benefits or special precautions required for individual subjects
or at-risk groups and any implications for the conduct of future studies should be identified.
Alternatively, such discussions may be reserved for summaries of safety and efficacy referring to
the entire dossier (integrated summaries).
14.
TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN
THE TEXT
Figures should be used to visually summarize the important results, or to clarify results that are
not easily understood from tables.
Important demographic, efficacy, and safety data should be presented in summary figures or tables
in the text of the report. However, if these become obtrusive because of size or number they
should be presented here, cross-referenced to the text, along with supportive, or additional,
figures, tables, or listings.
The following information may be presented in this section of the core clinical study report:
14.1
14.2
14.3
15.
REFERENCE LIST
A list of articles from the literature pertinent to the evaluation of the study should be provided.
35
16.
APPENDICES
This section should be prefaced by a full list of all Appendices available for the study report.
Where permitted by the regulatory authority, some of the following Appendices need not be
submitted with the report but need to be provided only on request.
The applicant should therefore clearly indicate those Appendices that are submitted with the
report.
N.B.: In order to have Appendices available on request, they should be finalized by the time of
filing of the submission.
16.1
Study Information
16.1.1 Protocol and protocol amendments.
16.1.2 Sample case report form (unique pages only).
16.1.3 List of IEC's or IRB's (plus the name of the committee chair if required by
the regulatory authority) and representative written information for patient and
sample consent forms.
16.1.4 List and description of investigators and other important participants in the
study, including brief (one page) CV's or equivalent summaries of training and
experience relevant to the performance of the clinical study.
16.1.5 Signatures of principal or coordinating investigator(s) or sponsor's
responsible medical officer, depending on the regulatory authority's requirement.
16.1.6 Listing of patients receiving test drug(s)/investigational product(s) from
specific batches, where more than one batch was used.
16.1.7 Randomization scheme and codes (patient identification and treatment
assigned).
16.1.8 Audit certificates (if available).
36
16.2
16.1.11.
16.1.12
16.3.
16.4
37
ANNEX I
SYNOPSIS
Name of Sponsor/Company:
Title of Study:
Investigators:
Study centre(s):
Publication (reference)
Phase of development:
Objectives:
Methodology:
Duration of treatment:
I-1
Name of Sponsor/Company:
Statistical methods:
SUMMARY - CONCLUSIONS
EFFICACY RESULTS :
SAFETY RESULTS:
CONCLUSION:
I-2
ANNEX II
PRINCIPAL OR COORDINATING
INVESTIGATOR(S) SIGNATURE(S)
OR SPONSOR S RESPONSIBLE MEDICAL OFFICER
STUDY TITLE:
STUDY AUTHOR(S):
_______________
..............................................................................
...
..............................................................................
...
I have read this report and confirm that to the best of my knowledge it accurately
describes the conduct and results of the study
INVESTIGATOR:______________________
OR SPONSORS RESPONSIBLE
MEDICAL OFFICER
SIGNATURE(S)____________
AFFILIATION:________________________
______________________
_______________________
DATE:______________________________
II-1
ANNEX IIIa
STUDY DESIGN AND SCHEDULE OF ASSESSMENTS
A
TREATMENT
PERIOD
Run-in
B1
B2
C1
C2
TEST DRUG/
INVESTIGATIONAL
A
PRODUCT
TEST DRUG/
INVESTIGATIONAL
PRODUCT A
5 mg
10 mg
5 mg
TEST DRUG/
INVESTIGATIONAL
B
PRODUCT
TEST DRUG/
INVESTIGATIONAL
PRODUCT B
5 mg
10 mg
5 mg
10 mg
10 mg
Weeks
-2(-3)
12
Visit
x2
x1
Exercise test 24 h
Medical history
Physical examination
ECG
Lab. invest.
Adverse events
IIIa-1
ANNEX IIIb
Assessment
Screening
Study Week
-2
Informed
Consent
History
Physical
Exam.
Runin
-1
Baseline
0
Treatment
1
Follow-up
4
Effectiveness
primary
variable
secondary
variable
Adverse
events
Lab. tests
Body weight
Safety
IIIb-1
x
x
N = 59
WITHDRAWN
N = 281
COMPLETED
STUDY
N = 340
REGIMEN A
N=
WITHDRAWN
N=
COMPLETED
STUDY
N=
REGIMEN B
N=
WITHDRAWN
IVa-1
N = 1,361
PATIENTS COMPLETING STUDY
N=
COMPLETED
STUDY
N=
REGIMEN C
N = 1,724
PATIENTS RECEIVING
DOUBLE-BLINDED MEDICATION
Disposition of Patients
N=
WITHDRAWN
N=
COMPLETED
STUDY
N=
REGIMEN D
N=
WITHDRAWN
N=
COMPLETED
STUDY
N=
REGIMEN E
ANNEX IVa
ANNEX IVb
DISPOSITION OF PATIENTS
N = 2670
PATIENTS SCREENED
N = 17320
PATIENTS RANDOMIZED
N =8
DID NOT RECEIVE
ANY MEDICATION
Reasons:
____________ (2)
____________ (4)
____________ (2)
N=
REGIMEN A
N=
COMPLETED
N=
WITHDRAWN
N = 938
Screening Failures
Reasons:
____________ (300)
____________ (271)
____________
N = 1724
PATIENTS RECEIVING
DOUBLE-BLIND
MEDICATION
N=
REGIMEN B
N=
COMPLETED
N=
WITHDRAWN
IVb-1
N=
REGIMEN C
N=
COMPLETED
N=
WITHDRAWN
ANNEX V
STUDY #
(Data Set Identification)
LISTING OF PATIENTS WHO DISCONTINUED THERAPY
Centre.:
Treatment
Patient#
Sex
Age
Last Visit
Duration Dose
Concomitant
Medication
Test Drug/
investigational product
Reason for
Discontin.
Adverse
reaction *
Therapy
failure
Treatment
Patient#
Sex
Age
Last Visit
Duration Dose
Concomitant
Medication
Sex
Age
Last Visit
Duration Dose
Concomitant
Medication
Reason for
Discontin.
Reason for
Discontin.
Active Control/
Comparator
Treatment
Patient#
Placebo
*
V-1
ANNEX VI
STUDY #
(Data Set Identification)
Listing of Patients and Observations Excluded from Efficacy Analysis
Center.:
Treatment Patient # Sex Age Observation Excluded Reason(s)
Test Drug/Investigational Product
Treatment Patient # Sex Age Observation Excluded Reason(s)
Active Control/Comparator
Treatment Patient # Sex Age Observation Excluded Reason(s)
Placebo
(Repeat for other centres)
Reference Tables
Summary:
VI-1
ANNEX VII
STUDY #
(Data Set Identification)
Number of Patients Excluded from Efficacy Analysis
Test Drug/Investigational Product N =
Reason
___1___
Week
___2___
________
________
________
________
________
________
________
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
Total
_______
___4___
___8___
VII-1
ANNEX VIII
GUIDANCE FOR SECTION 11.4.2 -- STATISTICAL/ANALYTICAL ISSUES
AND APPENDIX 16.1.9
A.
Statistical Considerations
Details of the statistical analysis performed on each primary efficacy variable should be presented
in Appendix 16.1.9. Details reported should include at least the following information:
(a)
The statistical model underlying the analysis. This should be presented precisely
and completely, using references if necessary.
(b)
A statement of the clinical claim tested in precise statistical terms, e.g., in terms of
null and alternative hypotheses.
(c)
The statistical methods applied to estimate effects, construct confidence intervals,
etc. Literature references should be included where appropriate.
(d)
The assumptions underlying the statistical methods. It should be shown, insofar as
statistically reasonable, that the data satisfy crucial assumptions, especially when necessary
to confirm the validity of an inference. When extensive statistical analyses have been
performed by the applicant, it is essential to consider the extent to which the analyses were
planned prior to the availability of data and, if they were not, how bias was avoided in
choosing the particular analysis used as a basis for conclusions. This is particularly
important in the case of any subgroup analyses, because if such analyses are not
preplanned they will ordinarily not provide an adequate basis for definitive conclusions.
(i)
In the event data transformation was performed, a rationale for the choice
of data transformation along with interpretation of the estimates of treatment
effects based on transformed data should be provided.
(ii)
A discussion of the appropriateness of the choice of statistical procedure
and the validity of statistical conclusions will guide the regulatory authority's
statistical reviewer in determining whether reanalysis of data is needed.
(e)
The test statistic, the sampling distribution of the test statistic under the null
hypothesis, the value of the test statistic, significance level (i.e., p-value), and intermediate
summary data, in a format that enables the regulatory authority's statistical reviewer to
verify the results of the analysis quickly and easily. The p-values should be designated as
one or two tailed. The rationale for using a one-tailed test should be provided.
VIII-1
For example, the documentation of a two-sample t-test should consist of the value of the
t-statistic, the associated degrees of freedom, the p-value, the two sample sizes, mean and
variance for each of the samples, and the pooled estimate of variance. The documentation
of multicenter studies analyzed by analysis of variance techniques should include, at a
minimum, an analysis of variance table with terms for centers, treatments, their interaction,
error, and total. For crossover designs, the documentation should include information
regarding sequences, patients within sequences, baselines at the start of each period,
washouts and length of washouts, dropouts during each period, treatments, periods,
treatment by period interaction, error, and total. For each source of variation, aside from
the total, the table should contain the degrees of freedom, the sum of squares, the mean
square, the appropriate F-test, the p-value, and the expected mean square.
Intermediate summary data should display the demographic data and response data,
averaged or otherwise summarized, for each center-by-treatment combination (or other
design characteristic such as sequence) at each observation time.
B.
Format and Specifications for Submission of Data Requested by Regulatory Authority's
Statistical Reviewers
In the report of each controlled clinical study, there should be data listings (tabulations) of patient
data utilized by the sponsor for statistical analyses and tables supporting conclusions and major
findings. These data listings are necessary for the regulatory authority's statistical review, and the
sponsor may be asked to supply these patient data listings in a computer-readable form.
VIII-2
Part 3
Submissions
SECTION 4
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
esub@cder.fda.gov
esub@cder.fda.gov
eCTD Changes
esub@cder.fda.gov
esub@cder.fda.gov
esub@cder.fda.gov
Submissions 101
esub@cder.fda.gov
Just say no
No paper unless required for original
signatures
No Word files or file formats not
specified in the guidance
No electronic submissions or records
sent directly to a reviewer or project
manager
No electronic desk copies
esub@cder.fda.gov
Just dont do it
Dont send electronic submissions to
the division document rooms
Dont use node extensions in preparing
eCTD
Dont combine multiple documents into
single PDF
Dont send customized style sheets
Dont hide your media place it in the
volume with your cover letter.
esub@cder.fda.gov
References
CDER Contact for information on eCTD
submissions
eSub@cder.fda.gov
esub@cder.fda.gov
SECTION 5
I.
TABLE OF CONTENTS
INTRODUCTION............................................................................................................. 1
II.
A.
Scope ............................................................................................................................................... 2
B.
C.
D.
E.
Electronic Submissions.................................................................................................................. 4
F.
G.
H.
I.
J.
K.
L.
Electronic Signatures..................................................................................................................... 6
O.
P.
File Formats.................................................................................................................................... 7
Q.
R.
S.
III.
A.
B.
C.
D.
IV.
A.
B.
Style Folder................................................................................................................................... 16
Technical specifications associated with this guidance will be provided as stand alone documents. They
will be updated periodically. To ensure that you have the most recent versions, check the appropriate
center's guidance Web page. For CBER, this Web site is http://www.fda.gov/cber/esub/esub.htm. For
CDER, this Web site is http://www.fda.gov/cder/regulatory/ersr/ectd.htm.
ii
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
An alternative approach may be used if such approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
I.
INTRODUCTION
This is one in a series of guidance documents intended to assist applicants making regulatory
submissions to the FDA in electronic format using the electronic common technical document
(eCTD) specifications. This guidance discusses issues related to the electronic submission of
applications for human pharmaceutical products2 and related submissions, including abbreviated
new drug applications (ANDAs), biologics license applications (BLAs), investigational new drug
applications (INDs), new drug application (NDAs), master files (e.g., drug master files),
advertising material, and promotional labeling.3 At this time, this does not include applications
supporting combination products.
We have revised this guidance, which was first published in October 2005, to correct the names
of the eCTD backbone and U.S. Regional backbone files referenced in section IV.A.
1
This guidance has been developed by the Center for Drug Evaluation and Research (CDER) and the Center for
Biologics Evaluation and Research (CBER).
Human pharmaceutical products include those products that meet the definition of drug under the Food, Drug and
Cosmetic Act, including those that are chemically synthesized and those derived from living sources (biologic
products).
3
Agency guidance documents on electronic submissions will be updated regularly to reflect the evolving nature of
the technology and the experience of those using this technology.
Paperwork Reduction Act of 1995: This guidance contains information collection provisions that are subject to
review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520). The collections of information in this guidance have been approved under OMB Control Nos. 09100014, 0910-0001, and 0910-0338.
GENERAL ISSUES
This portion of the guidance makes recommendations on general organizational issues related to
the electronic submission of applications for human pharmaceutical products using the cCTD
specifications. The requirements for the content of such applications are described in our
regulations in chapter 21 of the Code of Federal Regulations (CFR). Additional
recommendations on the contents of applications are provided in Agency guidances, which are
available on the Agency Web page.
A.
Scope
This document provides general guidance on how to organize application information for
electronic submission to the Agency using the eCTD specifications. Guidance on the information
to be included in the technical sections of applications and submissions is described in a series of
guidance documents based on the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) common technical
The recommendations made here on how to organize application information are based on the
ICH CTD and the electronic CTD (eCTD), which was developed by the ICH M2 expert working
group. Although the CTD and the eCTD were designed for marketing applications, they could
apply equally to other submission types, including INDs, master files, advertising material, and
promotional labeling.4 Details on the specification for the ICH eCTD can be found in the
guidance document M2 eCTD: Electronic Common Technical Document Specification.
D.
E.
Electronic Submissions
Under our regulations (21 CFR 11.2(b)(2)), applicants and sponsors are expected to contact us
for details on how to proceed with electronic submissions. These details are usually provided in
guidance documents. For example, we are already receiving marketing application submissions
for human pharmaceutical products in electronic format based on details provided in the
guidances for industry Providing Regulatory Submissions in Electronic Format NDAs,
Providing Regulatory Submissions in Electronic Format ANDAs, Providing Regulatory
Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format
Biologics Marketing Applications, and Providing Regulatory Submissions in Electronic
Format General Considerations.6 However, we recommend that you begin submitting eCTD
backbone files as described in this guidance because we believe that having the information in
the eCTD backbone files will result in greater efficiency in the future. In time, the other
guidances may be withdrawn because they may no longer be needed.
When we are ready to receive a particular submission type in electronic format only, we usually
identify it in public docket 92S-0251. Under 21 CFR part 11, you then have the option of
providing that submission type in electronic format according to FDA guidance so that the
Agency may adequately process, archive, and review the files.
Once you begin to submit a specific application in electronic format based on this guidance,
subsequent submissions to the application, including amendments and supplements, should
include eCTD backbone files. Without the eCTD backbone files, we will not be able to
adequately manage, process, archive, or review the submissions. If you choose to submit an
original application using the eCTD backbone files, you should obtain an application number in
advance by contacting the appropriate center. You may obtain the number at any time and the
numbers will not be reused.
We believe it is most beneficial to begin your eCTD-based submissions with the initial
submission of an application. Contact the appropriate center first if you wish to make eCTDbased submissions to pending applications. You should avoid the submission of any paper
documents when you follow the recommendations in this document. The maximum benefit will
be derived once an application is in electronic format. This is particularly true for the IND,
where submissions are provided over a long period of time. You should submit the electronic
information for all files in the eCTD backbone files following the specifications associated with
this guidance.
F.
If you decide to submit a specific application in electronic format based on this guidance, you do
not have to provide eCTD backbone files for the previous submissions to the application. For
example, if you submitted an original application in 2001 and now submit an amendment to the
application using the eCTD backbone files, you do not have to go back and submit the document
information for the files submitted in 2001.
6
G.
If a document was submitted in electronic format with the eCTD backbone files, you should not
submit additional copies when referencing the previously submitted document. Instead, you
should include the information by reference by providing in the text of the document (1) the
application or master file number, (2) the date of submission (e.g., letter date), (3) the document
name, and (4) the page number of the referenced document along with a hypertext link to the
location of the information (see section II.Q of this guidance). If a document replaces or appends
a document previously submitted with an eCTD backbone file, then you should include this
information in the appropriate eCTD backbone file. The details on how to include this
information in the eCTD backbone file are provided in the associated specifications for eCTD
backbone files.
If a document was previously submitted in either paper or electronic format without the proper
eCTD backbone files, you should reference the document as with any paper submission. In the
text of the document, you should include (1) the application or master file number, (2) the date of
submission (e.g., letter date), (3) the document name, (4) the page number, and (5) the
submission identification (e.g., submission serial number, volume number, electronic folder, and
file name) of the referenced document. In such cases, providing an electronic copy of the
previously submitted documents can increase the utility of the submission. These documents,
like all documents in the submission, should be appropriately described in the eCTD backbone
files. These files are considered new in the eCTD backbone files.
When referring to documents that are part of other applications, please remember to include the
appropriate letters of authorization with the submission (e.g., 21 CFR 314.420(d)).
H.
Refuse to File
We may refuse to file an application or supplement under our regulations (e.g., 21 CFR 314.101
and 601.2) if the submission is illegible, uninterpretable, or otherwise clearly inadequate,
including having incompatible formats or inadequate organization. These regulations apply to
both paper and electronic submissions. The absence of electronic datasets in an acceptable
format to permit review and analysis may be considered inadequate, resulting in a refuse-to-file
decision.8 Following the recommendations in this guidance document will help ensure that your
electronic application meets the requirements of FDA regulations and can be archived,
processed, and reviewed within specified time frames using our tools.
Previously submitted documents include previously submitted information by reference for master files, market
applications, and investigational applications discussed under 21 CFR 312.23(a)(11)(b), 314.50(g)(1), 314.420(b),
and 601.51(a).
When providing applications in electronic format using the eCTD backbone files, paper copies of
the application, including review copies and desk copies, are not required and should not be sent.
J.
Scanned Documents
Scanned documents submitted electronically as images are not as useful for review as documents
that are text based. Image-based documents are more difficult to read and cannot be
electronically searched. It takes longer to print image-based documents, and they occupy more
storage space than text-based documents. For these reasons, we strongly urge that you provide
text-based documents, rather than image files, whenever possible. We understand that certain
documents may only be available as image files. Handwritten documents and documents that
were generated independent from the company, such as journal publications, may be available
only in paper. Documents that may only be available in paper can be scanned and submitted in
electronic format as image-based files. However, we expect documents such as study reports
recently generated by the company or recently generated as the result of the company's request to
be available as text-based documents. We understand that legacy study reports, those generated
years ago, may only be available in paper. For these reports, especially those for pivotal studies,
you may want to consider converting these documents from image files to text-based files.
Optical Character Recognition that has been validated is an option.
K.
FDA District offices have access to documents submitted in electronic format. Therefore, when
sending submissions in electronic format, you need not provide any documentation to the FDA
Office of Regulatory Affairs District Office.
L.
Electronic Signatures
Documents required by regulations to be submitted with an original signature (e.g., FDA form
356h, FDA form 1571) should be submitted with electronic signatures that follow the controls
described under 21 CFR part 11.
M.
You should send a single copy of the electronic portions of a submission to the appropriate
central document room facility. Copies should not be sent directly to the reviewer or review
division. Electronic documents that bypass the controls for electronic files described in 21 CFR
11 are not considered official documents for review.
N.
To function properly, the eCTD backbone files must have specific names (e.g., index.xml,
us-regional.xml). For other files without a specified name, you should provide a name that is
indicative of the contents (e.g., protocol-101). The file name should allow a reviewer to infer
Naming Folders
The terms folder and subfolder are used in this guidance and are intended to be synonymous with
directory and subdirectory. The main submission, regional administrative folders, and certain
subfolders should have specific names for proper and efficient processing of the submission.
Recommendations regarding naming the main submission folders and regional administrative
folders can be found in section III, below. Other specific folder names can be found in the
specifications associated with this guidance. You can use only letters (lower case), numbers, or
hyphens in the name. You should not use blank spaces. The length of the folder name should not
exceed 64 characters. When naming folders, it is important to remember that the length of the
entire path should not exceed 230 characters. You should not include empty folders in the
submission.
P.
File Formats
We recommend that you send electronic documents in the file formats specified in this guidance.
We will not be able to manage, process, archive, or review documents provided in other file
formats.
The following file formats should be used:
In the future, we may consider other electronic file formats for use with electronic submissions,
or we may consider the use of the current formats with other electronic submissions. We intend
to publish guidance to advise on the use of file formats for specific types of submissions for use
in the future.
Q.
For documents with a table of contents, provide bookmarks and hypertext links for each item
listed in the table of contents including tables, figures, publications, references, and associated
appendices. These bookmarks and hypertext links are essential for efficient navigation through
documents. You should make the bookmark hierarchy identical to the table of contents.
Navigation efficiency is also improved by providing hypertext links throughout the body of the
document to supporting annotations, related sections, references, appendices, tables, or figures
that are not located on the same page.
It is possible to link to other documents in a submission using relative paths when creating
hypertext linking. Absolute links that reference specific drives and root directories are not
functional once the submission is loaded onto the document repository. For example, the link
path ../../../123456/0001/.. will work, but the link c:\123456\0001\ will not work. However,
you should keep in mind that some documents may be subsequently replaced or appended,
possibly rendering the link obsolete, so linking should be used cautiously.
When creating bookmarks and hypertext links, choose the magnification setting Inherit Zoom so
that the destination page displays at the same magnification level that the reviewer is using for
the rest of the document.
R.
All submissions provided in electronic format must be sent to the appropriate central document
room facility for processing to maintain the integrity of the submission as required under 21 CFR
part 11. Electronic documents sent directly to division document rooms or to reviewers bypass
the controls established for the receipt and archiving of documents and are not considered
official documents for review. See the associated specifications for more information, including
electronic transmission.
S.
If you have any questions on technical issues related to providing electronic submissions
according to the recommendations in this guidance, contact the electronic submission
coordinator at esub@cder.fda.gov. Specific technical issues related to submissions to CBER
should be sent to esubprep@cber.fda.gov. Specific questions pertaining to content should be
directed to the appropriate review division or office.
III.
All documents in the electronic submission should be placed in a main submission folder using a
four-digit sequence number for the application with the original submission for an application
designated 0000. You should assign numbers for each submission to the same application with
consecutive numbers. For example, the folder for the 3rd submission to an application, whether it
Module 1 contains administrative and labeling documents. The organization of the documents in
module 1 is the same for all applications and related submissions. The subject matter for each
document should be assigned to the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. Note that some
headings apply only to specific applications or specific submissions. You should create a folder
named us and place it in the folder named m1. The documents for module 1 should be placed in
the us folder including the us-regional.xml file pertaining to the eCTD backbone files for module
1. Below are some additional details on providing specific types of documents.
1.
The details on creating this file are in the associated document eCTD Backbone Files
Specification for Module 1.
2.
If you decide to include a cover letter, we recommend you include the following information:
3.
Labeling
Labeling history
You can provide a history summarizing labeling changes as a single PDF file. The
following information will help us confirm changes made to the labeling:
b.
Labeling samples
Each labeling sample (e.g., carton labels, container labels, package inserts) should
be provided as individual PDF files. The samples should (1) include all panels, if
applicable; (2) be provided in their actual size; and (3) reflect the actual color
proposed for use.
4.
In the postmarketing study commitments files, you should include a bookmark for each study
described.
6.
Information amendments
You should include documents that are provided in information amendments in the appropriate
module using the appropriate headings to describe the subject matter. In the unusual case when
information amendments do not fit appropriately under any heading in the CTD, you should
place the documents in module 1 under the heading information amendment: Information not
covered under modules 2 to 5. You should provide a separate PDF file for each subject
covered. Documents that apply to more than one module should be placed under the heading
Multiple module information amendments.
B.
You should place the documents for module 2 in the m2 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. Each document should
be provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic
Common Technical Document Specification are not necessary for the review of the submission.
If you choose to use the additional subfolder, we will maintain the subfolder structure so links
will function properly.
11
The organization of the module 3 folder is the same for all applications and related submissions.
You should place the documents for module 3 in the m3 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. Each document should
be provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic
Common Technical Document Specification are not necessary for the review of the submission.
If you choose to use the additional subfolder, we will maintain the subfolder structure used so
links will function properly.
You should provide the files pertaining to Key Literature References (CTD section 3.3) as
individual PDF files. The filenames should be short and meaningful.
D.
The organization of the module 4 folder is the same for all applications and related submissions.
You should place the documents for module 4 in the m4 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. The headings for study
reports should also be specific for the lowest level of the hierarchy. Each document should be
provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic
Common Technical Document Specification are not necessary for the review of the submission.
If you choose to use the additional subfolder, we will maintain the subfolder structure so links
will function properly.
1.
Study reports
Typically, a single document should be provided for each study report included in this module.
However, if you provide the study reports as multiple documents, you should confine the subject
matter of each document to a single item in the following list.
Synopsis
Study report body
Protocol and amendments
Signatures of principal or coordinating investigator(s)
Audit certificates and reports
Documentation of statistical methods and interim analysis plans
Documentation of interlaboratory standardization methods of quality assurance
procedures if used
Publications based on the study
Important publications referenced in the report
Compliance and/or drug concentration data
Individual subject data listings
Data tabulations
- Data tabulations datasets
12
When providing a study report, you should include the study tagging file (STF) described in the
associated document The eCTD Backbone File Specifcation for Study Tagging Files.
2.
Literature references
You should provide each literature reference as an individual PDF file. The filenames should be
short and meaningful.
3.
Datasets
See the associated document Study Data Specifications for details on providing datasets and
related files (e.g., data definition file, program files)
E.
The organization of the module 5 folder is the same for all applications and related submissions.
You should place the documents for module 5 in the m5 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the associated
document Comprehensive Table of Contents Headings and Hierarchy. One exception is that
legacy study reports can be provided as a single document. Each document should be provided as
an individual PDF file. The subfolders described in the guidance M2 eCTD: Electronic Common
Technical Document Specification are not necessary for the review of the submission. If you
13
You should provide the tabular listing of all clinical studies as a single PDF file.
2.
Study reports
Typically, clinical study reports are provided as more than one document based on the ICH E3
guidance document when providing a study.9 In addition, if you have provided a document in a
previous submission (e.g., protocol), you should provide a reference to the protocol rather than
resubmitting the protocol. In cases when a legacy report has already been prepared as a single
electronic document, you can provide the entire study report, other than the case report forms
(CRFs) and individual data listings, as a single document. The individual documents that should
be included in a study report are listed below:
Synopsis10 (E3 2)
Study report (E3 1, 3 to 15)
Protocol and amendments (E3 16.1.1)
Sample case report forms (E3 16.1.2)
List of IECs or IRBs (E3 16.1.3) and consent forms
List and description of investigators (E3 16.1.4) and sites
Signatures of principal or coordinating investigator(s) or sponsors responsible
medical officer (E3 16.1.5)
Listing of patients receiving test drug(s) from specified batch (E3 16.1.6)
Randomizations scheme (E3 16.1.7)
Audit certificates (E3 16.1.8) and reports
Documentation of statistical methods (E3 16.1.9) and interim analysis plans
Documentation of interlaboratory standardization methods of quality assurance
procedures if used (E3 16.1.10)
Publications based on the study (E3 16.1.11)
Important publications referenced in the report (E3 16.1.12)
Discontinued patients (E3 16.2.1)
Protocol deviations (E3 16.2.2)
Patients excluded from the efficacy studies (E3 16.2.3)
Demographic data (E3 16.2.4)
Compliance and/or drug concentration data (E3 16.2.5)
Individual efficacy response data (E3 16.2.6)
Adverse event listings (E3 16.2.7)
Listing of individual laboratory measurements by patient (E3 16.2.8)
When providing a study report, you should include the study tagging file (STF) described in the associated
document The eCTD Backbone File Specification for Study Tagging Files.
10
The synopsis should be provided as a document separate from the study report.
14
3.
You should provide an individual subjects complete CRF as a single PDF file. If a paper CRF
was used in the clinical trial, the electronic CRF should be a scanned image of the paper CRF
including all original entries with all modifications, addenda, corrections, comments,
annotations, and any extemporaneous additions. If electronic data capture was used in the
clinical trial, you should submit a PDF-generated form or other PDF representation of the
information (e.g., subject profile).
You should use the subjects unique identifier as the title of the document and the file name.
These names are used to assist reviewers in finding the CRF for an individual subject. Each CRF
must have bookmarks as part of the comprehensive table of contents required under
21 CFR 314.50(b). We recommend bookmarks for each CRF domain and study visit to help the
reviewer navigate the CRFs. For addenda and corrections, making a hypertext link from the
amended item to the corrected page or addendum is a useful way to avoid confusion. Bookmarks
for these items should be displayed at the bottom of the hierarchy.
4.
Datasets
See the associated document Study Data Specifications for details on providing datasets and
related files (e.g., data definition files, program files). For subject profiles, you should use the
subjects unique identifier in the title of the document and the file name.
5.
To facilitate electronic submissions, we have divided the postmarketing periodic adverse drug
experience report into three parts: (1) individual case safety reports (ICSRs), (2) ICSR
attachments, if applicable, and (3) descriptive information. The descriptive information includes
15
Literature references
You should provide each literature reference as an individual PDF file. The filenames should be
short and meaningful.
IV.
UTILITY FOLDER
You should create two folders, dtd and style and place them in the util folder.
A.
You should place the document type definition (DTD) that you used to create the eCTD
backbone file (index.xml), the DTD you used to create the FDA Regional eCTD backbone file
(us-regional.xml), and the DTD used for the STF in the folder named dtd. You should use the
most recent DTD.11
B.
Style Folder
You should use the most recent stylesheet. See the guidance for industry M2 eCTD: Electronic
Common Technical Document Specification.
11
Part 4
Technical Requirements
SECTION 6
This section includes the complete structure and numbering for content headings and
the hierarchy of Modules 15.
Revision History
Date
Version
Summary of Changes
2004-07
1.0
Original version
2005-06-16
1.1
Corrections and additions to the mapping tables
2005-07-06
1.2
Corrections to the headings
Module 2 Summaries
2.2 Introduction to summary
2.3 Quality overall summary
2.4 Nonclinical overview
2.5 Clinical overview
2.6 Nonclinical written and tabulated summaries
2.6.1 Introduction
2.6.2 Pharmacology written summary
2.6.3 Pharmacology tabulated summary
2.6.4 Pharmacokinetic written summary
2.6.5 Pharmacokinetic tabulated summary
Module 3 Quality
3.2 Body of data
3.2.S Drug Substance [name, manufacturer]
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General properties
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
3.2.S.2.2 Description of Manufacturing Process and Process
Controls
3.2.S.2.3 Control of Materials
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and/or Evaluation
3.2.S.2.6 Manufacturing Process Development
3.2.S.3 Characterization
3.2.S.4.1 Specification
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justification of Specification
3.2.P.4.1 Specification(s)
3.2.P.4.2 Analytical Procedures
3.2.P.4.3 Validation of Analytical Procedures
3.2.P.4.4 Justification of Specifications
3.2.P.4.5 Excipients of Human or Animal Origin
3.2.P.4.6 Novel Excipients
3.2.P.5.1 Specification(s)
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of Analytical Procedures
3.2.P.5.4 Batch Analyses
3.2.P.5.5 Characterization of Impurities
3.2.P.5.6 Justification of Specification(s)
3.2.A Appendices
3.2.A.1 Facilities and Equipment [name,
manufacturer]
3.2.A.2 Adventitious Agents Safety Evaluation [name,
dosage form, manufacturer]
3.2.A.3 Novel Excipients
3.2.R Regional Information
3.3Literature references
4.2.2 Pharmacokinetics
4.2.2.1 Analytical methods and validation reports
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4.2.2.5 Excretion
4.2.3 Toxicology
4.2.3.1 Single dose toxicity [Species and route]
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
Study report [identification number] and related
information
See Primary pharmacodynamics Study
report and related information for heading
4.2.3.3.2 In vivo
Study report [identification number] and related
information
4.2.3.4 Carcinogenicity
4.2.3.7.1 Antigenicity
Study report [identification number] and related
information
See Primary pharmacodynamics Study
report and related information for heading
4.2.3.7.2 Immunotoxicity
Study report [identification number] and related
information
4.2.3.7.4 Dependence
Study report [identification number] and related
information
4.2.3.7.5 Metabolites
Study report [identification number] and related
information
4.2.3.7.6 Impurities
Study report [identification number] and related
information
4.2.3.7.7 Other
10
11
Mapping
IND
CFR Citation/Source
NUMBER
TITLE
FDAMA
FDAMA
FDAMA
PDUFA
agreements
FDAMA
PDUFA
agreements
PDUFA
agreements
PREA
PREA
BPCA
BPCA
Mod
ule
1
1.7.1
1.7.2
1.7.3
1.7.5
Special protocol
assessment request:
Clinical study
Special protocol
assessment request:
Carcinogenicity Study
Special protocol
assessment request:
Stability study
Request for waiver of
pediatric studies
Request for deferral of
pediatric studies
Proposed Proposed
pediatric study request
and amendments
Proposal for Written
Agreement
1.8.1
1.8.1
1.8.1
1.9.1
1.9.2
1.9.4
1.9.5
12
PREA
BPCA
312.7(d)(1)
312.10
312.23(a)1
312.23(a)(2)
312.23(a)(3)(i)
312.23(a)(3)(iiiii)
312.23(a)(3)(iv)
312.23(a)(5)
312.23(a)(6)
312.23(a)(7)(a),
(b) and (c)
312.23(a)(7)(a),
(b) and (c)
312.23(a)7(d)
312.23(a)(7)(iv)(
e)
312.23(a)(8)
312.23(a)(8)
312.23(a)(8)
312.23(a)(9)
312.23(a)(9)
312.23(a)(9)
Correspondence
regarding pediatric
exclusivity or PREA
requirements
Charging for and
commercialization of
investigational drugs
Waivers
Cover sheet (Form FDA
1571).
Table of contents
Introductory statement
1.9.6
1.12.3
1
1
1.12.5
1.1.1
Correspondence
regarding pediatric
exclusivity or study
plans
Request to charge
Request for a waiver
Application form:
FDA form 1571
N/A
Introduction to
summary
Clinical overall
summary
General investigational
plan
Investigator brochure
*Protocol [under
specific study]
Quality overall
summary
N/A
2
N/A
2.2
Introductory statement
2.5
1.13.9
1
5
1.14.4.1
5.3
2.3
As needed
Quality [use
appropriate sections]
1.14.4.2
Environmental analysis
requirements
Pharmacology and
toxicology information
Pharmacology and
toxicology information
1.12.14
Investigational Drug
Labeling
Environmental analysis
2.4
Nonclinical overview
2.6
Pharmacology and
toxicology information
Previous human
experience
Previous human
experience
Previous human
experience
4.2
2.5
2.7
5.3
Chemistry,
manufacturing and
controls
Chemistry,
manufacturing and
controls
Labeling
13
312.23(a)(10)(i)
312.23(a)(10)(ii)
2.7.4
2, 4
or 5
2, 3,
4 or 5
1, 2,
3, 4
or 5
1
As needed
1, 2,
3, 4,
or 5
5
As needed
5.3
As needed
312.23(a)(11)
Relevant information
312.23(b)
312.30(a)
Information previously
submitted by sponsor
Material in a foreign
language (English
Translations)
New protocol
312.30(b)
Changes in protocol
5.3
312.30(c)
New investigator
5.3
312.31(a)(1),
Information amendment:
Chemistry
Information amendment:
Chemistry -information
not covered under
Module 3
As needed
1.11.1
Information amendment:
Toxicology
Information amendment:
Toxicology - information
not covered under
Module 4
As needed
1.11.2
Information amendment:
Clinical
Information amendment:
Clinical - information not
covered under Module 5
As needed
1.11.3
1.12.9
1.2
312.23(c)
312.31(a)(1)
312.31(a)(1)
312.31(a)(1)
312.31(a)(1)
312.31(a)(1)
312.31(a)(2)
312.31(b)(1)
14
As needed
1.4.4
Summary of Clinical
Safety
Use appropriate
sections
Use appropriate
sections
Use appropriate
sections
Cross reference to other
applications
Use appropriate
sections
Protocol [under
specific study]
Protocol [under
specific study]
List and description of
investigators and sites
[under specific study]
Use appropriate
sections
Quality information
amendment (only for
information not
covered under Module
3
Use appropriate
sections
Safety information
amendment (only for
information not
covered under Module
4)
Use appropriate
sections
Efficacy information
amendment (only for
information not
covered under Module
5
Notification of
discontinuation of
clinical trial
Cover letter
312.31(b)(3)
312.32
312.33(a)
312.33(b)(1)
312.33(b)(2)
312.33(b)(3)
312.33(b)(4)
312.33(b)(5)
312.33(b)(6)
312.33(b)(7)
312.33(b)(7)
312.33(c)
312.33(e)
1.12.4
5.3
1.13.8
1.13.3
1.13.3
Summary of safety
information
1.13.3
1.13.3
Summary of safety
information
Summary of safety
information
1.13.2
1.13.1
1.13.5
1.13.5
Summary of
microbiological
changes
1.13.9
General investigational
plan
5.3
Summary of clinical
pharmacology
information
Summary of
nonclinical studies
Summary of
manufacturing changes
312.33(d)
312.33(f)
312.33(g)
312.35(a)(1)
312.35(a)(2)(i)
312.35(a)(2)(ii)
312.35(a)(2)(iii)
312.36
Annual Report:
Investigators brochure
Annual Report: A brief
summary of significant
foreign marketing
developments
Annual Report: Log of
outstanding
business(optional)
Treatment protocol
Treatment protocol:
Investigators brochure
Treatment protocol:
Technical information
Treatment protocol:
Compliance with
informed consent
Emergency use of an
investigational new drug
312.38
Withdrawal of an IND
312.41
312.45(a)
312.45(d)
312.47
PDUFA
Agreements
312.47
PDUFA
Agreements
312.47
PDUFA
Agreements
312.48
FDAMA
312.48
FDAMA
312.52
1.14.4.1
Investigator brochure
1.13.10
Foreign marketing
history
1.13.14
Log of outstanding
regulatory business
5.3
1.14.4.1
*Protocol [under
specific study]
Investigator brochure
3, 4,
5
5
As needed
1, 2,
3, 4,
5
1
As Needed
5.3
Use appropriate
sections
*List and description of
investigators and sites
[under specific study]
Use appropriate
sections
1.5.1
Withdrawal Request
1.12.4
1.5.2
Request to resume
clinical investigation
under an inactive IND
Meeting request
1.5.3
Reactivation Request
1.6.1
Meeting request
Meeting background
material
1.6.2
Meeting background
material
Correspondence
regarding a meeting
1.6.3
Correspondence
regarding a meeting
1.10.1
1.10.2
1.3.1.3
16
contract research
organization.
312.54
1.12.6
312.54
Public disclosure
exception from informed
consent for research
1.12.7
312.54
IRB disapproval of
exception from informed
consent for research
1.12.8
312.120(b)(1)
5.3
5.3
5.3
As needed
5.3
312.120(b)(2)
312.120(b)(3)
312.120(b)(4)
312.120(c)
NDA
CFR Citation/Source
NUMBER
TITLE
FDAMA
Fast Track Designation
Request
FDAMA
Fast Track Designation
Withdrawal Request
FDAMA
Rolling Review
Request
FDAMA
Correspondence
regarding Fast
Track/Rolling Review
PDUFA
Rolling Review
17
Module
1
1
1
1
1
Exception from
informed consent for
research
Public disclosure
statement for exception
from informed consent
for research
Correspondence
regarding exception
from informed consent
for research
*List and description of
investigators and sites
[under specific study]
*List and description of
investigators and sites
[under specific study]
Use appropriate
sections [under specific
study]
Use appropriate
sections
agreements
314.50(a)
Request
Application form
1.1.2
PDUFA
1.1.3
GDEA
Debarment
Certification
Request for waiver of
pediatric studies
Request for deferral of
pediatric studies
Request for pediatric
exclusivity
determination
Proposed pediatric
study request and
amendments
Proposal for written
agreement
Correspondence
regarding pediatric
exclusivity or PREA
requirements
Index
The proposed text of
the labeling with
annotations
Summaries
1.3.3
1.9.1
1.9.2
1.9.3
1.9.4
1.9.5
1.9.6
PREA
PREA
BPCA
BPCA
BPCA
PREA
BPCA
315.50(b)
314.50(c)(2)(i)
314.50(c)(2)(ii)
to (ix)
314.50(d)(1)(i)
and (ii)
314.50(d)(4)
Chemistry,
manufacturing and
controls
Environmental impact
Field copy certification
Nonclinical
pharmacological and
toxicology section
Human
pharmacokinetics and
bioavailability sections
Microbiology
314.50(d)(5)(i)
314.50(d)(1)(iii)
314.50(d)(1)(v)
314.50(d)(2)
314.50(d)(3)
18
N/A
1
N/A
1.14.1.2
As needed
As needed
1
1
4
1.12.14
1.3.2
As needed
Environmental analysis
Field copy certification
Use appropriate
sections
5.3
Use appropriate
sections
5.3.5.5
5.3
to (iv)
314.50(d)(5)(v)
An integrated summary
of efficacy
5.3.4
314.50(d)(5)(vi)(
a)
An integrated summary
of safety
5.3.4
314.50(d)(5)(vi)(
b)
Safety Update
5.3.5
314.50(d)(5)(vii)
5.3
314.50(d)(5)(viii
)
314.50(d)(5)(ix)
2.5
314.50(d)(5)(xi)
An integrated summary 2
of the benefits and risks
Statement of
5
compliance with
informed consent
Transfer of obligations
to CRO
Audited studies
314.50(d)(6)(i)
and (ii)
Description of
statistical analysis
314.50(d)(7)
2 and 5
As needed
314.50(e)(2)(i)
Analytical methods
As needed
314.50(e)(2)(ii)
1.14
5.3
314.50(d)(5)(x)
314.50(f)(1)
19
5.3
1
1.3.1.4
5.3
5.3
sections
Reports of analysis of
data from more than
one study [Use
appropriate sections in
integrated summary of
efficacy STF]
Reports of analysis of
data from more than
one study [Use
appropriate sections in
integrated summary of
safety STF]
Reports of analysis of
data from more than
one study [Use
appropriate sections in
integrated summary of
safety STF]
Use appropriate
sections
Use appropriate
sections
*List of IECs or IRBs
and consent forms
[under specific study]
Transfer of obligation
*Audit certificates and
reports [under specific
study]
*Documentation of
statistical methods and
interim analysis plans
[under specific study]
Use appropriate
sections
Use appropriate
sections
Use appropriate
sections
*Case report
tabulations [use the
appropriate sections
under the specific
study]
*Case report forms
[under the appropriate
site and specific study]
Letter of authorization
314.50(f)(2)
5.3
314.50(g)(1)
Written statement of
authorization for
references
Reference to
information previously
submitted by sponsor
1.4.1
1.4.4
Statement of right of
reference
Patent Information
1.4.2
1.3.5.1
Patent certification
1.3.5.2
Claimed exclusivity
Financial certification
and disclosure
statement
Pediatric studies:
waiver of pediatric
study requirements
Pediatric studies:
deferrals of pediatric
study requirements
Amendment to an
unapproved
application: Chemistry
Amendment to an
unapproved
application: Chemistry
(information not
covered under Module
3)
Amendment to an
unapproved
application: Toxicology
Amendment to an
unapproved
application: Toxicology
(information not
covered under Module
4)
1
1
1.3.5.3
1.3.4
Exclusivity claim
Financial certification
and disclosure
1.9.1
1.9.2
As needed
Use appropriate
sections
1.11.1
Quality information
amendment (only for
information not
covered under Module
3)
As needed
Use appropriate
sections
1.11.2
Safety information
amendment (only for
information not
covered under Module
4)
314.50(g)(1)
314.50(g)(1)
314.50(h)
314.53(b)
314.50(i)
314.52(b)
314.50(j)
314.50(k)
PREA
PREA
314.60
314.60
314.60
314.60
20
314.60
Amendment to an
unapproved
application: Clinical
314.60
Amendment to an
unapproved
application: Clinical
(information not
covered under Module
5)
314.65
Withdrawal of an
unapproved application
314.70 and
Supplements and other
314.71
changes to approved
applications
314.72
Change of ownership
of an application
314.80(2)(ii)(a) Periodic adverse drug
314.80(2)(ii)(c) experience narrative
summary and history of
actions
314.81(b)(1)
Field alert reports
314.81(b)(2)
Annual report
transmittal: FDA form
2252
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
314.81(b)(2)(i)
Annual Report:
Summary
As needed
Use appropriate
sections
1.11.3
Efficacy information
amendment (only for
information not
covered under Module
5
1.5.5
Withdrawal of an
unapproved application
Use the appropriate
sections
1, 2, 3,
4, 5
As needed
1.3.1.4
5.3.6
1
1
1.12.16
1.1.4
1.13.1
1.13.2
1.13.3
1.13.4
1.13.5
1.13.6
314.81(b)(2)(i)
Annual Report:
Summary
1.13.7
314.81(b)(2)(ii)
Annual Report:
Distribution data
Annual Report:
Labeling
Annual Report:
Chemistry,
1.13.11
1.14
As needed
314.81(b)(2)(iii)
314.81(b)(2)(iv)
21
Change in ownership of
an application
Postmarketing periodic
adverse event drug
experience report
description
Field alert reports
Annual Report
Transmittal: FDA form
2252
Summary of
nonclinical changes
Summary of clinical
pharmacology changes
Summary of safety
changes
Summary of labeling
changes
Summary of
manufacturing changes
Summary of
microbiological
changes
Summary of other
significant new
information
Distribution data
Use appropriate
sections
Use appropriate
sections
314.81(b)(2)(v)
314.81(b)(2)(vi)
314.81(b)(2)(vii)
314.81(b)(2)(viii
)
314.81(b)(2)(ix)
314.81(b)(3)(i)
314.81(b)(3)(i)
314.90
314.102
314.102
314.102
314.103(c)
314.103(c)
314.150(c)
314.150(b)
314.420(a)
314.420(b)
manufacturing and
controls
Annual Report:
Nonclinical laboratory
studies
Annual Report:
Clinical data
Annual Report: Status
report of clinical and
nonclinical toxicology
postmarketing study
commitments
Status report of other
(chemistry,
manufacturing,
controls) postmarketing
study commitments
Annual Report: Log of
outstanding regulatory
business
Advertising and
promotional labeling
Transmittal of
Advertisements and
Promotional Labeling
Waivers
Communications:
Meetings
Communications:
Meetings
Communications:
Meetings
Scientific and medical
disputes
Scientific and medical
disputes
Request for withdrawal
of approval
Withdrawal or
suspension of approval
by the FDA
Drug master files
Incorporating DMF
information by
22
As needed
Use appropriate
sections
As needed
1.13.12
1.13.13
Use appropriate
sections
Status report of
clinical and nonclinical
toxicology
postmarketing study
commitments
Status of other
postmarketing study
commitments
1.13.14
Log of outstanding
regulatory business
1.15
Promotional material
1.1.5
1
1
1.12.5
1.6.1
Advertisements and
promotional labeling
transmittal: FDA form
2253
Request for a waiver
Meeting request
1.6.2
1.6.3
1.10.1
1.10.2
1.5.7
1.5.7
1, 2, 3,
4, 5
1
As Needed
1.4.1
Meeting background
materials
Correspondence
regarding meetings
Request for dispute
resolution
Correspondence related
to dispute resolution
Request for withdrawal
of application approval
Other correspondence
regarding status of
application or product
Use appropriate
sections
Letter of Authorization
314.420(d)
314.550
314.640
reference
List of authorized
persons to incorporate
by reference
Subpart H: Promotional
materials
Subpart I: Promotional
materials
ANDA
CFR Citation/Source
NUMBER
TITLE
314.94(a)(1)
Application form
GDEA
314.94(a)(4)
Debarment
Certification
Table of Contents
Basis for abbreviated
new drug application
submission
Conditions for use
314.94(a)(5)
314.94(a)(6)
314.94(a)(2)
314.94(a)(3)
1.4.3
1.15
List of authorized
persons to incorporate
by reference
Promotional material
1.15
Promotional material
Module
1
1
N/A
1
1.11.11
Active ingredient
1.11.12
1.11.12
314.94(a)(7)
Route of
administration, dosage
form and strength
Bioequilvance
5.3
314.94(8)(i)
1.14.3.2
314.94(8)(ii)
Copies of proposed
labeling
Statement of proposed
labeling
Comparison of
approved and proposed
labeling
Chemistry,
manufacturing and
control
Reference to
information previously
submitted by sponsor
Patent certification
Notice of certification
1.14
1.14.3.1
1.14.3.1
As needed
Use appropriate
sections
1.4.4
1
1
1.3.5.2
1.3.5.3
Patent certification
Certification of non-
314.94(8)(iii)
314.94(8)(iv)
314.94(9)
314.94(11)
314.94(12)
314.95
23
314.94(13)
314.96
314.96
314.96
314.96
314.102
314.102
314.102
314.103(c)
314.103(c)
314.150(c)
314.150(b)
314.151
314.420(a)
314.420(b)
314.420(d)
24
1.3.4
As needed
1.11.1
Quality information
amendment
As needed
Use appropriate
sections
1.11.3
Efficacy information
amendment
1.6.1
Meeting request
1.6.2
1.6.3
1.10.1
1.10.2
1.5.7
1.5.7
Meeting background
materials
Correspondence
regarding meetings
Request for dispute
resolution
Correspondence related
to dispute resolution
Request for withdrawal
of an application
Other correspondence
regarding status of
application or product
Use appropriate
sections
Letter of Authorization
1, 2, 3,
4, 5
1
1
As needed
1.4.1
1.4.3
List of authorized
persons to incorporate
by reference
SECTION 7
Conformance
Review Checklist
For NDAs
Appl_Type Appl_No
Drug_Name
Sponsor_Applicant
January 1999
TABLE OF CONTENTS
I.
INTRODUCTION................................................................................................... 3
II.
FOLDERS .............................................................................................................. 3
COVER LETTER..................................................................................................... 3
356H FORM .......................................................................................................... 4
NDA TABLE OF CONTENTS .................................................................................. 4
FIGURE OF MAIN FOLDER ..................................................................................... 4
INTRODUCTION
GENERAL ISSUES
A.
Refuse to File
B.
The Archival Copy
If portions of the NDA archival copy are submitted in paper and electronic
format, the index (commonly referred to as the table of contents) for the
submission must include the location of the paper documents by volume number
and electronic files by file and folder name(s) so the index is comprehensive.
C.
Providing a Review Copy
D.
The Field Copy
E.
Supplements and Amendments
F.
Electronic Signatures
Until those procedures are in place, documents for which regulations require an
original signature, such as certifications, must be accompanied by a paper copy
that includes the handwritten signature and the NDA number.
G.
Review Aids
Provide all review aid files on floppy disks or CDROMs and secure them in a
standard binder marked clearly on the outside REVIEW AIDS NOT FOR
ARCHIVE. Include the review aids in the appropriate technical section of the
review copy.
III.
All documents and datasets for the electronic archival copy should be placed in a main
folder using the NDA number (e.g., N123456) as the folder name.
A.
Folders
Inside the main folder, all of the documents and datasets should be organized by
the NDA items described on page 2 of FDA form 356h.
B.
Cover Letter
You should provide a cover letter as a PDF file named cover.pdf inside the main
folder. The cover letter should include the following:
Folder name
main folder
labeling
summary
cmc
pharmtox
hpbio
micro
clinstat
update
clinstat
crt
crf
other
other
other
other
other
other
other
C.
356h Form
You should provide FDA form 356h as a PDF file named 356h.pdf inside the main
folder. On page 2 of the form, you should note next to each item if the documents for the
item are in paper format, electronic format, or both paper and electronic format.
D.
NDA Table Of Contents
Inside the main folder, the applicant should provide a table of contents for the submission
named ndatoc.pdf. See item 1 below for additional information.
E.
Figure of Main Folder
The following is an example of the contents of the main folder for NDA 123456.
772
IV.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
B.
1
n/a
n/a
1-4
5-10
main folder
Labeling
Summary
n/a
Pharmtox
n/a
Hpbio
n/a
n/a
n/a
n/a
n/a
n/a
n/a
1
n/a
1
1
1
n/a
Micro
Clinstat
n/a
Clinstat
Crt
Crf
Other
Other
n/a
Other
Other
Other
Other
Item 2: Labeling
1.
Folder
You should place all documents for this item in a single folder named labeling.
2.
Table of contents
3.
Labeling history
4.
Labeling text
Document Information fields should contain the following information: (use only
lower case letters).
C.
D.
5.
Package insert
6.
Carton labeling
7.
Container labeling
8.
Other
Item 3: Summary
1.
Folder
2.
Table of contents
3.
Summary document
4.
Bookmarks and hypertext linking
Item 4: Chemistry, Manufacturing, and Control (CMC)
1.
Folders
2.
Table of contents
You must provide a table of contents listing all files provided in the CMC item as
a PDF file named cmctoc.pdf. This table of contents is considered part of the
comprehensive table of contents required in 314.50(b).
7
3.
Drug substance
4.
Drug product
5.
Investigational formulations
6.
Environmental assessment
7.
Methods validation
8.
Batch records
9.
Publications
10.
Bookmarks and hypertext links
For all documents with a table of contents, you must provide bookmarks for each
item in the documents table of contents including all tables, figures, publications,
and appendices. These bookmarks serve as part of the comprehensive table of
contents for the submission and, therefore, are required under 314.50(b).
11.
Full text index
An index of the full text and the Document Information fields of all documents in
this section should be provided. Name the index definition file cmcindex.pdx.
Place all associated index files in a folder named cmcindex. Place the
cmcindex.pdx definition file and the cmcindex subfolder in the main cmc folder.
Associate the cmctoc.pdf file with the index file so that whenever the table of
contents file is opened, the associated index is automatically added to the
available index list.
E.
2.
Table of contents
You must provide a table of contents listing all study reports (including study
report numbers), publications, and the summary provided in the pharmtox section
as a PDF file named pharmtoc.pdf. If datasets are provided for a study, you
should note this in the table of contents. This table of contents is considered part
of the comprehensive table of contents required in 314.50(b).
3.
Summary document
4.
Study reports
3.
Summary
G.
4.
Study reports
5.
Datasets
6.
Publications
7.
Bookmarks and hypertext links
For all documents with a table of contents, you must provide bookmarks for each
item in the documents table of contents including all tables, figures, publications,
and appendices including datasets, if applicable. These bookmarks serve as part
of the comprehensive table of contents for the submission and, therefore, are
required under 314.50(b). If datasets are provided with the study, you should
include a bookmark to the appropriate data definition file (define.pdf).
8.
Full text index
Item 7: Clinical Microbiology
1.
Folders
2.
Table of contents
You must provide a table of contents listing all reports and publications for this
section as a PDF file named microtoc.pdf. If datasets are provided for a study,
you should note this in the table of contents. Place this file in the micro folder.
This table of contents is considered part of the comprehensive table of contents
(314.50(b)).
3.
Summary document
4.
Study reports
5.
Datasets
6.
Publications
7.
Bookmarks and hypertext links
As part of a comprehensive table of contents for the submission, you must provide
bookmarks for each item in the documents table of contents including all tables,
figures, and appendices including datasets, if applicable (314.125(b)). If datasets
are provided with a report, you should include a bookmark to the appropriate data
definition file (define.pdf).
8.
Full text index:
H.
Item 8: Clinical
1.
Folders
10
778
I.
J.
K.
2.
Table of contents
You must provide a table of contents listing all files in this section. Provide the
table of contents as a PDF file; name this file clintoc.pdf and place it in the
clinstat folder. We consider the table of contents to be part of the comprehensive
table of contents (314.50(b)).
3.
Study reports
Because files 50 MB or larger are technically more difficult to handle, study
reports that are larger than 50 MB should be divided into two PDF files.
4.
Integrated summaries
5.
Publications
6.
Bookmarks and hypertext links
For all documents with a table of contents, you must provide bookmarks for each
item in the documents table of contents including all tables, figures, publications,
and appendices including datasets. For datasets, you should include a bookmark
to the appropriate data definition file (define.pdf). These bookmarks serve as part
of the comprehensive table of contents for the submission and, therefore, are
required under 314.50(b).
7.
Full text index
Item 9: Safety Update
1.
Folders
All documents for this section should be placed in a single folder named update
and a single PDF file provided for each document.
2.
Table of contents
A table of contents for all files in this section must be provided in the form of a
PDF file as part of the comprehensive table of contents (314.125(b)). The
organization of the table of contents should follow the guidance provided in item
8. Name the PDF file updattoc.pdf and place it in the update folder.
3.
Full text index
Item 10: Statistical For electronic submissions, item 8 and item 10 are identical.
Item 11: Case Report Tabulations (CRTs)
CRTs are item 11 on page 2 of FDA form 356h.
You should provide CRTs in datasets allowing the reviewers to use their own software
for analysis. Each dataset is a single file and, in general, includes a combination of raw
and derived data.
11
In addition to electronic datasets, study data collected for individual patients, organized
by time, can be provided in PDF files. We call this collection of data a patient profile,
and it serves as an adjunct to the electronic datasets. Patient profiles are not meant to be
a replacement for electronic datasets.
1.
Format of the datasets
You should provide each dataset as a SAS transport file as described in the
companion guidance, Regulatory Submissions in Electronic Format General
Considerations (January 1999
Dataset files should be organized so that their size is generally less than 25 MB
per file. The files should not be compressed. Each dataset should be saved as an
individual file.
The data variable names should be no more than 8 characters in length because of
restrictions in our data format. We recommend that you provide a more
descriptive data variable label, up to 32 characters in length.
2.
Organization of data
3.
Documentation of the datasets
You should include two PDF files, one of the data definition tables (define.pdf)
and one of the annotated case report forms (blankcrf.pdf) to describe the datasets
for each study, specific data analysis (e.g., population PK), and integrated
summaries.
4.
Dataset table of contents
The dataset table of contents is also part of the comprehensive table of contents
and must list all studies and integrated summaries that have datasets. You must
provide a hypertext link to the appropriate data definition table file (314.50(b)).
The table of contents should be provided as a PDF file named datatoc.pdf and
placed in the datasets folder.
5.
Full text index
6.
General considerations for datasets
7.
Patient profiles as PDF files
a.
Folders
b.
Table of contents
You must provide in a PDF file a table of contents listing all patient profiles by
study. Name this file protoc.pdf. This table of contents is considered part of the
comprehensive table of contents (314.50(b)). List the patient identification
numbers by study, site, and treatment assignment and describe the location of the
patient profile with the file name and folder(s). Provide a hypertext link between
the documents listed in the table of contents and the corresponding PDF file and
bookmarks for each item in the table of contents. Place the protoc.pdf file in the
profile folder.
c.
Patient profiles
You should provide each individual patients complete patient profile as a single
PDF file. Including the patient ID in the file name will help identify the file.
12
d.
e.
L.
Item 12: Case Report Forms
If a paper CRF was used in the clinical trial, the electronically submitted CRF should be
an exact image or series of images of the paper CRF that contains all original entries with
all modifications, addenda, corrections, comments, annotations, and any extemporaneous
additions. For data collected electronically, all data collected for an individual patient
should be organized by domain and time and provided as a PDF file. This presentation is
the same as a patient profile described in item 11 (CRTs). This file should subsequently
be handled the same as an imaged CRFs.
1.
Folders - You should create a folder for each study to organize the CRFs.
2.
Table of contents
You must provide a table of contents listing all case report forms provided by
study, site and treatment assignment as a PDF file. Name this file crftoc.pdf.
This table of contents is considered part of the comprehensive table of contents
(314.50(b)). List the patient identification numbers by study, site and treatment
assignment and describe the location of the case report forms with the file name
and folder(s). Provide a hypertext link between the documents listed in the table
of contents and the corresponding PDF file and bookmarks for each item in the
table of contents. Place the crftoc.pdf file in the crf folder.
3.
Case report forms
You should provide each individual patients complete CRF as a single PDF file.
Including the patient ID in the file name will help identify the file. Place the PDF
files in the appropriate study site folder. For example, all CRFs for site 001 for
13
study 101 would be placed into a folder named 001, which then would be placed
in a folder named 101.
The Document Information Title field for each file should include the letters crf,
the study number, the site identification, and the patients unique ID number. The
unique patient ID number should be composed of elements of the study number,
site number, and patient number, or a functional equivalent. For example, the
CRF for patient 001 in study 2001 at site 003 would have the following in the
Title field: crf, study 2001, site 003, PID 2001-003-001.
4.
Bookmarks and hypertext links
Each CRF must have bookmarks as part of the comprehensive table of contents
required under 314.50(b).
5.
Full text index
An index of the full text and the Document Information field of all documents in
the crf folder should be provided. Even if all of the CRFs are images, the text in
the Document Information field should be indexed. The index definition file
should be named crfindex.pdx. Place all associated index files in a folder named
crfindex. Place the crfindex.pdx definition file and the crfindex subfolder in the
main crf folder. Associate crftoc.pdf with the index file so that whenever the
table of contents file is opened, the associated index is automatically added to the
available index list.
M.
14
N.
O.
There should be a hypertext link from the submission table of contents directly to
the patinfo.pdf file.
3.
Patent information
You should provide the information pertaining to the patent information in a
single PDF file named patinfo.pdf.
Item 14: Patent Certification
1.
Folder
You should place the document for this section in the folder named other.
2.
Table of contents
There should be a hypertext link from the submission table of contents directly to
the patcert.pdf file.
3.
Patent certification
You should provide the information pertaining to the patent certification in a
single PDF file named patcert.pdf.
Item 15: Establishment Description (CBER only)
Item 15 on page 2 of FDA form 356h applies only to submissions to CBER.
P.
Q.
R.
15
S.
The user fee cover sheet should be provided as a single PDF file named
userfee.pdf.
Item 19: Other
1.
Folder
You should place all additional information for this item in the folder named
other.
2.
Table of contents
There should be a hypertext link from the submission table of contents directly to
each file in this item.
3.
Other items
You should provide each additional item as a separate PDF file
16
SECTION 8
This document provides specifications for creating the eCTD backbone file
for Module 1 for use with the guidance to industry: Providing Regulatory
Submissions in Electronic Format Human Pharmaceutical Applications
and Related Submissions.
Summary of Changes
Original version
Clarifications to the original version
Change to Related Sequence Example
Change to XML coding for a supplement to an original application
related sequence example
TABLE OF CONTENTS
I.
START OF
II.
V.
Forms..........................................................................................................................................................9
Cover Letters ............................................................................................................................................10
Administrative Information.......................................................................................................................10
Reference Section .....................................................................................................................................11
Application Status Documentation ...........................................................................................................12
Meetings ...................................................................................................................................................13
Fast Track.................................................................................................................................................13
Special Protocol Assessment Request.......................................................................................................14
Pediatric Administrative Information.......................................................................................................14
Dispute Resolution....................................................................................................................................15
Information Not Covered Under Modules 2 to 5 ......................................................................................15
Other Correspondence .............................................................................................................................16
Annual Report...........................................................................................................................................18
Labeling....................................................................................................................................................20
Promotional Material ...............................................................................................................................23
Risk Management Plans ...........................................................................................................................23
Applicant-info Element
The application-info elements contains the applicant-info element: company-name, and date-ofsubmission.
0. Company-name Element
The sponsor or applicants name is in the company-name element. An example of the companyname element for the VeryBest Drug Company with its content is provided:
<company-name>VeryBest Drug Company</company-name>
You should provide this element with every submission.
0. Date-of-submission Element
1
Both the start tag and the end tag of the admin element should be placed between the start and end tags of the:fdaregional element.
Version 1.3
Product-description Element
There are two elements contained in the product-description element: application-number, and
prod-name.
0. Application-number Element
The 6 digit application number in placed in the application-number element. You should
provide only the digits, including any leading zeros for the application number without letters or
dashes. An example of the application-number element for NDA 99-999 with its content is
provided:
<application-number>099999</application-number >
You should provide this element with every sequence number submission to the application.
0. Prod-name Element
The prod-name elements contains up to four different types of product name, all of which can
occur in a single submission. Provide an attribute for the prod-name element named type.
Indicate the type of product name you contained in the prod-name element by choosing one of
the four allowed values. The table below lists the available product name types (type attribute
values) with their meaning:
type Attribute and Value
type="established"
type="proprietary"
type="chemical"
type="code"
Version 1.3
Application-information Element
The element application-information contains the submission element. You should provide an
attribute for the application-information element named application-type. Indicate the type of
application for this submission in the application-type element by choosing one of the types
allowed. The table below lists the available application types (application-type attribute values)
with their meaning:
application-type Attribute and Value
application-type="nda"
application-type="anda"
application-type="bla"
application-type="ind"
application-type="dmf"
Application Type
New Drug Application
Abbreviated New Drug Application
Biologics License Application
Investigational new drug application.
Master file
0. Submission Element
There are two elements in the submission element: sequence-number, and related-sequencenumber. You should provide a submission-type attribute for the submission element that contains
the value for the type of submission from the following table:
Submission-type
Attribute Value
original-application"
"amendment"
"resubmission"
"presubmission"
"annual-report"
Version 1.3
Meaning
A complete new application that has never before been submitted
All submissions to pending original submission or pending
supplements to approved applications including responses to
information request letters
A complete response to an action letter, or submission of an
application that has been the subject of a withdrawal or a refusal to
file
Information submitted prior to the submission of a complete new
application
Annual Reports to applications
"labeling-supplement"
"chemistrymanufacturing-controlssupplement"
"other"
Meaning
Supplements to the information contained in the establishment
description section for biological products
Submissions for such changes as a new indication or dosage regimen
for an approved product, a comparative efficacy claim naming
another product, or a significant alteration in the patient population;
e.g., prescription to Over-The-Counter switch
All label change supplements required under 21 CFR 314.70 and 21
CFR 601.12 that do not qualify as efficacy supplements;
Manufacturing and Controls Supplement manufacturing change
supplement submissions as provided in 21 CFR 314.70, 21 CFR
314.71, 21 CFR 314.72 and 21 CFR 601.12
Not among those listed above
) Sequence-number Element
You should include the sequence number of the submission in the sequence-number element.
The sequence number should be exactly 4 digits with no spaces between them. You should
provide a sequence-number element with every submission. Note that sequence numbers are
used to differentiate between submissions for the same application and do not necessarily
correspond to the order they are received by the Agency. An example of the first application
sequence number element with its content is provided:
<sequence-number>0000</sequence-number>
) Related-sequence-number Element
When providing an amendment to an earlier submission, you should include the sequence
number of the earlier submission in the related-sequence-number element. The sequence
number should be exactly 4 digits with no spaces between them. If this submission is related to
more than one previous submission, you should provide each previous submission's sequence
number in a separate related-sequence-number element. There is no limit to the number of
related-sequence-number elements. The following is an example of the related sequence
number. An application has the following submissions:
0000
0001
0002
0003
0004
0005
0006
0007
- Original application
- an amendment to original application
- an amendment to original application
- a chemistry, manufacturing and control supplement
- an amendment to original application
- an amendment to the supplement
- an amendment to the original application
- an amendment that relates to both the original and supplement
Version 1.3
Sequence-number
0000
0001
0002
0003
0004
0005
0006
0007
Related-sequence-number***
0000
0000
0000
0003
0000
0000 0003
Example XML coding for the original application would look like:
<submission submission-type="original-application">
<sequence-number>0000</sequence-number>
</submission>
Example XML coding for a supplement to an original application would look like:
<submission submission-type="chemistry-manufacturing-controls-supplement ">
<sequence-number>0003</sequence-number>
</submission>
Example XML coding for a submission element of an amendment that would apply to two or
more original submissions, such as sequence number 0007 above, would look like:
<submission submission-type="chemistry-manufacturing-controls-supplement">
<sequence-number>0007</sequence-number>
<related-sequence-number>0000</related-sequence-number>
<related-sequence-number>0003</related-sequence-number>
</submission>
Example XML coding for an amendment to an original application or original supplement
(example shown is for an amendment to the original application):
<submission submission-type="amendment">
<sequence-number>0002</sequence-number>
<related-sequence-number>0000</related-sequence-number>
</submission>
III. LEAF ELEMENT
Information for an individual document is contained in the leaf element, its attributes and its
"title" element. The leaf element is used repeatedly throughout the eCTD backbone files to
provide individual information for each document being submitted. Detailed descriptions of
each part of the leaf element and how to use them are found in the document The eCTD
Version 1.3
Module 1 Heading
Regional information
0. Forms
Choose one of the following elements to contain
your form's leaf element.
)
Investigational New
Drug (IND)
) New Drug Application
(NDA) or New Biologic
Application (BLA)
Version 1.3
) Annual Report
Transmittal
) Advertising and
Promotional Labeling
) Transmittal of Labels
and Circulars
0. Cover Letters
End of Forms
0. Administrative Information
) Applicant Information
<m1-3-1-1-cofa-con>
<leaf>
</leaf>
</m1-3-1-1-cofa-con>
<m1-3-1-2-change-contactagent>
<leaf>
</leaf>
</m1-3-1-2-change-contactagent>
<m1-3-1-3-change-sponsor>
<leaf>
</leaf>
</m1-3-1-3-change-sponsor>
<m1-3-1-4-transfer-obligation>
<leaf>
</leaf>
</m1-3-1-4-transferobligation>
Version 1.3
10
Version 1.3
11
<m1-3-5-1-patent-information>
<leaf>
</leaf>
</m1-3-5-1-patentinformation>
<m1-3-5-2-patentcertification>
<leaf>
</leaf>
</m1-3-5-2-patentcertification>
<m1-3-5-3-exclusivityrequest>
<leaf>
</leaf>
</m1-3-5-3-exclusivityrequest>
</m1-3-5-patent-exclusivity>
</m1-3-administrative-information>
<m1-4-references>
) Statement of Right to
Reference
) List of Authorized to
Persons to Incorporate by
Reference
) Cross Reference to
Other Applications
0. Application
Documentation
End References
Status
) Withdrawal Request
) Inactivation Request
) Reactivation Request
) Reinstatement Request
Version 1.3
12
) Withdrawal of Listed
Drug
0. Meetings
) Meeting Request
) Meeting Background
Materials
) Correspondence
Regarding Meetings
0. Fast Track
End Meetings
Version 1.3
13
0. Special
Request
) Clinical Study
) Carcinogenicity Study
) Stability Study
Administrative
Version 1.3
14
) Proposed Pediatric
Study Request and
amendments
) Other Correspondence
Regarding Pediatric
Exclusivity or Study Plans
End Pediatric
0. Dispute Resolution
) Request for Dispute
Resolution
) Correspondence Related
to Dispute Resolution
Version 1.3
15
) Safety Information
Amendment
) Efficacy Information
Amendment
) Multiple Module
Information Amendments
End Modules
0. Other Correspondence
) Pre IND
Correspondence
) Request to Charge
) Notification of Charging
Under Treatment IND
Version 1.3
16
) Exemption from
Informed Consent for
Emergency Research
) Public Disclosure
Statement for Emergency
Care Research
) Correspondence
Regarding Emergency Care
Research
) Notification of
Discontinuation of Clinical
Trial
) Generic Drug
Enforcement Act Statement
Version 1.3
17
) Comparison of Generic
Drug and Reference Listed
Drug
) Environmental Analysis
End of correspondence
0. Annual Report
) Summary for
Nonclinical Studies
Version 1.3
18
) Summary of Safety
Information
) Summary of Labeling
Changes
) Summary of
manufacturing changes
) Summary of
microbiological changes
) Summary of Other
Significant New
Information
) Individual Study
Information
Version 1.3
19
) Foreign Marketing
History
) Distribution Data
) Status of Postmarketing
Study Commitments
) Status of Other
Postmarketing Studies
) Log of Outstanding
Regulatory Business
0. Labeling
) Draft Labeling
Version 1.3
20
) Final Labeling
(0) Final Carton or Container Labels
Version 1.3
21
) Investigational Drug
Labeling
) Foreign Labeling
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>
<!ELEMENT title (#PCDATA)>
<!ATTLIST title
ID ID #IMPLIED
>
<!ELEMENT link-text (#PCDATA | xref)*>
<!ATTLIST link-text
ID ID #IMPLIED
>
<!ELEMENT xref EMPTY>
<!ATTLIST xref
ID ID #IMPLIED
xmlns:xlink CDATA #FIXED "http://www.w3c.org/1999/xlink"
xlink:type CDATA #FIXED "simple"
xlink:role CDATA #IMPLIED
xlink:title CDATA #REQUIRED
xlink:href CDATA #REQUIRED
xlink:show (new | replace | embed | other | none) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none) #IMPLIED
>
<!ELEMENT node-extension (title, (leaf | node-extension)+)>
<!ATTLIST node-extension
ID ID #IMPLIED
xml:lang CDATA #IMPLIED
>
<!-- ================== ADMIN ==================================== -->
<!ELEMENT admin (applicant-info, product-description, application-information)>
<!-- ********************* Applicant Information ******************** -->
<!ELEMENT applicant-info (company-name, date-of-submission)>
<!ELEMENT company-name (#PCDATA)>
<!ELEMENT date-of-submission (date)>
<!ELEMENT date (#PCDATA)>
<!ATTLIST date
format (yyyymmdd) #REQUIRED
>
<!-- ********************* Product Description ********************** -->
<!ELEMENT product-description (application-number, prod-name+)>
<!ELEMENT application-number (#PCDATA)>
<!ELEMENT prod-name (#PCDATA)>
<!ATTLIST prod-name
type (established | proprietary | chemical | code) #REQUIRED
>
<!-- ********************* Application Information ****************** -->
<!ELEMENT application-information (submission)>
<!ATTLIST application-information
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>
<!ELEMENT submission (sequence-number, related-sequence-number*)>
<!ATTLIST submission
submission-type (
original-application |
amendment |
resubmission |
presubmission |
annual-report |
establishment-description-supplement |
efficacy-supplement | labeling-supplement |
chemistry-manufacturing-controls-supplement |
other) #REQUIRED
>
<!ELEMENT sequence-number (#PCDATA)>
<!ELEMENT related-sequence-number (#PCDATA)>
<!-- ================= M1 REGIONAL STRUCTURE ==================== -->
<!ELEMENT m1-regional (
m1-1-forms?,
m1-2-cover-letters?,
m1-3-administrative-information?,
m1-4-references?,
m1-5-application-status?,
m1-6-meetings?,
m1-7-fast-track?,
m1-8-special-protocol-assessment-request?,
m1-9-pediatric-administrative-information?,
m1-10-dispute-resolution?,
m1-11-information-amendment?,
m1-12-other-correspondence?,
m1-13-annual-report?,
m1-14-labeling?,
m1-15-promotional-material?,
m1-16-risk-management-plans?)>
<!ATTLIST m1-regional
%att;
>
<!-- ================= FORMS ==================================== -->
<!ELEMENT m1-1-forms (
m1-1-1-fda-form-1571?,
m1-1-2-fda-form-356h?,
m1-1-3-fda-form-3397?,
m1-1-4-fda-form-2252?,
m1-1-5-fda-form-2253?,
m1-1-6-fda-form-2567?)>
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>
<!ELEMENT m1-10-1-request-for-dispute-resolution ((leaf | node-extension)*)>
<!ATTLIST m1-10-1-request-for-dispute-resolution
%att;
>
<!ELEMENT m1-10-2-correspondence-related-to-dispute-resolution ((leaf | node-extension)*)>
<!ATTLIST m1-10-2-correspondence-related-to-dispute-resolution
%att;
>
<!-- ================ INFORMATION ADMENDMENT =================== -->
<!ELEMENT m1-11-information-amendment (
m1-11-1-quality-information-amendment*,
m1-11-2-safety-information-amendment*,
m1-11-3-efficacy-information-amendment*,
m1-11-4-multiple-module-information-amendments*)>
<!ATTLIST m1-11-information-amendment
%att;
>
<!ELEMENT m1-11-1-quality-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-1-quality-information-amendment
%att;
>
<!ELEMENT m1-11-2-safety-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-2-safety-information-amendment
%att;
>
<!ELEMENT m1-11-3-efficacy-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-3-efficacy-information-amendment
%att;
>
<!ELEMENT m1-11-4-multiple-module-information-amendments
((leaf | node-extension)*)>
<!ATTLIST m1-11-4-multiple-module-information-amendments
%att;
>
<!-- =============== OTHER CORRESPONDENCE ===================== -->
<!ELEMENT m1-12-other-correspondence (
m1-12-1-pre-ind-correspondence*,
m1-12-2-request-charge*,
m1-12-3-notification-charging-under-treatment-ind*,
m1-12-4-request-comments-advice-ind*,
m1-12-5-request-waiver*,
m1-12-6-exemption-informed-consent-emergency-research*,
m1-12-7-public-disclosure-statement-emergency-care-research*,
m1-12-8-correspondence-regarding-emergency-care-research*,
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SECTION 9
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.
Summary of Changes
Original version
Clarifications to the original version
I.
II.
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
Version 1.1
</leaf>
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
You should provide an ID attribute and value for each leaf element that is unique for the
submission.
C. Operation attribute for the leaf element
The purpose of the operation attribute is to provide a machine-readable indication of the effect
this leaf has on a leaf included in previously submitted eCTD backbone files.
You should include an operation attribute for each leaf you are submitting. The value for the
operation attribute is limited to: new, append, replace, and delete. The table below summarizes
the meaning of each modified-file attribute value.
Attribute and Value
operation ="new"
operation ="append"
operation ="replace"
operation ="delete"
Meaning
This means that the leaf does not have an effect on a leaf included in
previously submitted eCTD backbone files.
This means that the file contained in the current leaf provides
information that is in addition to information in a file contained in a
leaf previously submitted eCTD backbone file. If there are a series of
files appending an original file, only append the original file. You
should not append a file that append another file.
This means the file contained in the current leaf replaces a file
contained in a leaf in a previously submitted eCTD backbone file.
This means a file contained in a leaf in a previously submitted eCTD
backbone file should no longer be considered in the evaluation of the
application. In this situation, there is no file provided for the leaf.
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<m5-3-5-reports-of-efficacy-and-safety-studies>
manufacturer
substance
dosageform
product-name
indication
Each of the heading element attributes for the eCTD backbone file is described in detail in the
section of this appendix associated with the CTD module where the element and its attribute
occur.
The heading elements and heading element attributes for modules 2 through 5 are described
below.
A. Heading elements attributes for Module 2
This section describes the heading elements and attribute values relevant to module 2.
1. Heading elements
The module 2 heading elements are summarized in the following table. In some cases, the CTD
may describe more subheadings than appear on this table. Those subheadings should be used as
bookmarks within the individual document. Both the start tag and end tag for each heading
element are provided. If there are one or more subheadings for the heading, the corresponding
element end tag will occur on the table row below the last relevant subheading. The leaf element
is included to show where the leaf elements should be placed. The details for the leaf elements
are not shown on this table to keep it clearer. The leaf elements should only occur where
indicated in this table. A heading element may contain any number of leaf elements. If no
documents are submitted for a heading, you should omit the element for that heading in the
eCTD backbone file.
Module 2 CTD Heading
Module 2: Common Technical
Document (CTD) Summaries
2.2 CTD Introduction
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<m2-6-1-introduction>
<leaf>
</leaf>
</m2-6-1-introduction>
2.6.2 Pharmacology Written
<m2-6-2-pharmacology-written-summary>
Summary
<leaf>
</leaf>
</m2-6-2-pharmacology-written-summary>
2.6.3 Pharmacology Tabulated <m2-6-3-pharmacology-tabulated-summary>
Summary
<leaf>
</leaf>
</m2-6-3-pharmacology-tabulated-summary>
2.6.4 Pharmacokinetics Written <m2-6-4-pharmacokinetics-written-summary>
Summary
<leaf>
</leaf>
</m2-6-4-pharmacokinetics-written-summary>
2.6.5 Pharmacokinetics
<m2-6-5-pharmacokinetics-tabulated-summary>
Tabulated Summary
<leaf>
</leaf>
</m2-6-5-pharmacokinetics-tabulated-summary>
2.6.6 Toxicology Written
<m2-6-6-toxicology-written-summary>
Summary
<leaf>
</leaf>
</m2-6-6-toxicology-written-summary>
2.6.7 Toxicology Tabulated
<m2-6-7-toxicology-tabulated-summary>
Summary
<leaf>
</leaf>
</m2-6-7-toxicology-tabulated-summary>
End NWTS
</m2-6-nonclinical-written-and-tabulated-summaries>
Module 2: Clinical Overview
<m2-5-clinical-overview>
<leaf>
</leaf>
</m2-5-clinical-overview>
Module 2: Clinical Summary (CS)
<m2-7-clinical-summary>
2.7.1 Summary of
<m2-7-1-summary-of-biopharmaceutic-studies-andBiopharmaceutic
associated-analytical-methods>
Studies and Associated
<leaf>
Analytical Methods
</leaf>
</m2-7-1-summary-of-biopharmaceutic-studies-andassociated-analytical-methods>
2.7.2 Summary of Clinical
<m2-7-2-summary-of-clinical-pharmacology-studies>
Pharmacology Studies
</m2-7-2-summary-of-clinical-pharmacology-studies>
2.7.3 Summary of Clinical
<m2-7-3-summary-of-clinical-efficacy
Efficacy
indication="">
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3.2.S.1.2 Structure
eCTD Element
<m3-quality>
<m3-2-body-of-data>
<m3-2-s-drug-substance
substance=""
manufacturer="">7
<m3-2-s-1-general-information>
<m3-2-s-1-1-nomenclature>
<leaf>
</leaf>
</m3-2-s-1-1-nomenclature>
<m3-2-s-1-2-structure>
<leaf>
</leaf>
</m3-2-s-1-2-structure>
<m3-2-s-1-3-general-properties>
<leaf>
</leaf>
</m3-2-s-1-3-general-properties>
</m3-2-s-1-general-information>
<m3-2-s-2-manufacture>
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3.2.S.2.2 Description of
Manufacturing
3.2.S.3.2 Impurities
End Characterization
3.2.S.4 Control of Drug Substance
Version 1.1
eCTD Element
<m3-2-s-2-1-manufacturer>
<leaf>
</leaf>
</m3-2-s-2-1-manufacturer>
<m3-2-s-2-2-description-of-manufacturing-process-andprocess-controls>
<leaf>
</leaf>
</m3-2-s-2-2-description-of-manufacturing-process-andprocess-controls>
<m3-2-s-2-3-control-of-materials>
<leaf>
</leaf>
</m3-2-s-2-3-control-of-materials>
<m3-2-s-2-4-controls-of-critical-steps-andintermediates>
<leaf>
</leaf>
</m3-2-s-2-4-controls-of-critical-steps-andintermediates>
<m3-2-s-2-5-process-validation-and-or-evaluation>
<leaf>
</leaf>
</m3-2-s-2-5-process-validation-and-or-evaluation>
<m3-2-s-2-6-manufacturing-process-development>
<leaf>
</leaf>
</m3-2-s-2-6-manufacturing-process-development>
</m3-2-s-2-manufacture>
<m3-2-s-3-characterisation>
<m3-2-s-3-1-elucidation-of-structure-and-othercharacteristics>
<leaf>
</leaf>
</m3-2-s-3-1-elucidation-of-structure-and-othercharacteristics>
<m3-2-s-3-2-impurities>
<leaf>
</leaf>
</m3-2-s-3-2-impurities>
</m3-2-s-3-characterisation>
<m3-2-s-4-control-of-drug-substance>
15
3.2.S.4.5 Justification of
Specification
End Control of Drug Substance
3.2.S.5 Reference Standards or
Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability
3.2.S.7.1 Stability Summary and
Conclusions
3.2.S.7.2 Postapproval Stability
Protocol and Stability
Commitment
End Stability
Version 1.1
eCTD Element
<m3-2-s-4-1-specification>
<leaf>
</leaf>
</m3-2-s-4-1-specification>
<m3-2-s-4-2-analytical-procedures>
<leaf>
</leaf>
</m3-2-s-4-2-analytical-procedures>
<m3-2-s-4-3-validation-of-analytical-procedures>
<leaf>
</leaf>
</m3-2-s-4-3-validation-of-analytical-procedures>
<m3-2-s-4-4-batch-analyses>
<leaf>
</leaf>
</m3-2-s-4-4-batch-analyses>
<m3-2-s-4-5-justification-of-specification>
<leaf>
</leaf>
</m3-2-s-4-5-justification-of-specification>
</m3-2-s-4-control-of-drug-substance>
<m3-2-s-5-reference-standards-or-materials>
<leaf>
</leaf>
</m3-2-s-5-reference-standards-or-materials>
<m3-2-s-6-container-closure-system>
<leaf>
</leaf>
</m3-2-s-6-container-closure-system>
<m3-2-s-7-stability>
<m3-2-s-7-1-stability-summary-and-conclusions>
<leaf>
</leaf>
</m3-2-s-7-1-stability-summary-and-conclusions>
<m3-2-s-7-2-post-approval-stability-protocol-andstability-commitment>
<leaf>
</leaf>
</m3-2-s-7-2-post-approval-stability-protocol-andstability-commitment>
<m3-2-s-7-3-stability-data>
<leaf>
</leaf>
</m3-2-s-7-3-stability-data>
</m3-2-s-7-stability>
16
eCTD Element
</m3-2-s-drug-substance>
<m3-2-p-drug-product
product-name=""
dosageform=""
manufacturer="">8
<m3-2-p-1-description-and-composition-of-the-drugproduct>
</m3-2-p-1-description-and-composition-of-the-drugproduct>
3.2.P.2 Pharmaceutical Development <m3-2-p-2-pharmaceutical-development>
<leaf>
</leaf>
</m3-2-p-2-pharmaceutical-development>
3.2.P.3 Manufacture
<m3-2-p-3-manufacture>
3.2.P.3.1 Manufacturers
<m3-2-p-3-1-manufacturers>
<leaf>
</leaf>
</m3-2-p-3-1-manufacturers>
3.2.P.3.2 Batch Formula
<m3-2-p-3-2-batch-formula>
<leaf>
</leaf>
</m3-2-p-3-2-batch-formula>
3.2.P.3.3 Description of
<m3-2-p-3-3-description-of-manufacturing-process-andManufacturing Process and
process-controls>
Process Controls
<leaf>
</leaf>
</m3-2-p-3-3-description-of-manufacturing-process-andprocess-controls>
3.2.P.3.4 Controls of Critical
<m3-2-p-3-4-controls-of-critical-steps-andSteps and Intermediates
intermediates>
<leaf>
</leaf>
</m3-2-p-3-4-controls-of-critical-steps-andintermediates>
3.2.P.3.5 Process Validation
<m3-2-p-3-5-process-validation-and-or-evaluation>
and/or Evaluation
<leaf>
</leaf>
</m3-2-p-3-5-process-validation-and-or-evaluation>
End Manufacture
</m3-2-p-3-manufacture>
3.2.P.4 Control of Excipients
<m3-2-p-4-control-of-excipients
excipient="">9
8
9
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eCTD Element
<m3-2-p-4-1-specifications>
<leaf>
</leaf>
</m3-2-p-4-1-specifications>
<m3-2-p-4-2-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-4-2-analytical-procedures>
<m3-2-p-4-3-validation-of-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-4-3-validation-of-analytical-procedures>
<m3-2-p-4-4-justification-of-specifications>
<leaf>
</leaf>
</m3-2-p-4-4-justification-of-specifications>
<m3-2-p-4-5-excipients-of-human-or-animal-origin>
<leaf>
</leaf>
</m3-2-p-4-5-excipients-of-human-or-animal-origin>
<m3-2-p-4-6-novel-excipients>
<leaf>
</leaf>
</m3-2-p-4-6-novel-excipients>
</m3-2-p-4-control-of-excipients>
<m3-2-p-5-control-of-drug-product>
<m3-2-p-5-1-specifications>
<leaf>
</leaf>
</m3-2-p-5-1-specifications>
<m3-2-p-5-2-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-5-2-analytical-procedures>
<m3-2-p-5-3-validation-of-analytical-procedures>
<leaf>
</leaf>
</m3-2-p-5-3-validation-of-analytical-procedures>
<m3-2-p-5-4-batch-analyses>
<leaf>
</leaf>
</m3-2-p-5-4-batch-analyses>
18
3.2.P.8 Stability
3.2.P.8.1 Stability Summary and
Conclusion
3.2.P.8.2 Postapproval Stability
Protocol and Stability
Commitment
End Stability
End Drug Product
3.2.A APPENDICES
3.2.A.1 Facilities and Equipment
10
eCTD Element
<m3-2-p-5-5-characterisation-of-impurities>
<leaf>
</leaf>
</m3-2-p-5-5-characterisation-of-impurities>
<m3-2-p-5-6-justification-of-specifications>
<leaf>
</leaf>
</m3-2-p-5-6-justification-of-specifications>
</m3-2-p-5-control-of-drug-product>
<m3-2-p-6-reference-standards-or-materials>
<leaf>
</leaf>
</m3-2-p-6-reference-standards-or-materials>
<m3-2-p-7-container-closure-system>
<leaf>
</leaf>
</m3-2-p-7-container-closure-system>
<m3-2-p-8-stability>
<m3-2-p-8-1-stability-summary-and-conclusion>
<leaf>
</leaf>
</m3-2-p-8-1-stability-summary-and-conclusion>
<m3-2-p-8-2-post-approval-stability-protocol-andstability-commitment>
<leaf>
</leaf>
</m3-2-p-8-2-post-approval-stability-protocol-andstability-commitment>
<m3-2-p-8-3-stability-data>
<leaf>
</leaf>
</m3-2-p-8-3-stability-data>
</m3-2-p-8-stability>
</m3-2-p-drug-product>
<m3-2-a-appendices>
<m3-2-a-1-facilities-and-equipment
manufacturer=""
substance=""
dosageform=""
product-name="">10
<leaf>
</leaf>
</m3-2-a-1-facilities-and-equipment
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End Appendices
3.2.R REGIONAL INFORMATION
End Quality
eCTD Element
<m3-2-a-2-adventitious-agents-safety-evaluation
manufacturer=""
substance=""
dosageform=""
product-name="">11
<leaf>
</leaf>
</m3-2-a-2-adventitious-agents-safety-evaluation>
<m3-2-a-3-excipients>
<leaf>
</leaf>
</m3-2-a-3-excipients>
</m3-2-a-appendices>
<m3-2-r-regional-information>
<leaf>
</leaf>
</m3-2-r-regional-information>
</m3-2-body-of-data>
<m3-3-literature-references>
<leaf>
</leaf>
</m3-3-literature-references>
</m3-quality>
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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>
<m3-2-p-drug-product
product-name="Cure All"
dosageform="Injection"
manufacturer="China Plant 1 DMF-0000001">
<m3-2-p-4-control-of-excipients
excipient="corn syrup">
<m3-2-p-4-1-specifications>
<leaf></leaf>16
</m3-2-p-4-1-specifications>
<m3-2-p-4-2-analytical-procedures>
<leaf></leaf>17
</m3-2-p-4-2-analytical-procedures>
<m3-2-p-4-4-justification-of-specifications>
<leaf></leaf>18
</m3-2-p-4-4-justification-of-specifications>
</m3-2-p-4-control-of-excipients>
</m3-2-p-drug-product>
</m3-quality>
You should provide an excipient attribute value for every Control of Excipients heading element.
There is no limit to the number of Control of Excipients heading elements. There is no limit to
the number of leaf elements the Control of Excipients heading element can contain.
d) Attributes for Appendix Elements
The heading elements for the Facilities and Equipment heading, <m3-2-a-1-facilities-andequipment> and for the Adventitious Agents Safety Evaluation heading, <m3-2-a-216
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4.2.1.2 Secondary
Pharmacodynamics
4.2.1.3 Safety Pharmacology
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
Version 1.1
eCTD Element
<m4-nonclinical-study-reports>
<m4-2-study-reports>
<m4-2-1-pharmacology>
<m4-2-1-1-primary-pharmacodynamics>
<leaf>
</leaf>
</m4-2-1-1-primary-pharmacodynamics>
<m4-2-1-2-secondary-pharmacodynamics>
<leaf>
</leaf>
</m4-2-1-2-secondary-pharmacodynamics>
<m4-2-1-3-safety-pharmacology>
<leaf>
</leaf>
</m4-2-1-3-safety-pharmacology>
<m4-2-1-4-pharmacodynamic-drug-interactions>
<leaf>
</leaf>
</m4-2-1-4-pharmacodynamic-drug-interactions>
</m4-2-1-pharmacology>
<m4-2-2-pharmacokinetics>
<m4-2-2-1-analytical-methods-and-validationreports>
<leaf>
</leaf>
</m4-2-2-1-analytical-methods-and-validationreports>
<m4-2-2-2-absorption>
<leaf>
</leaf>
</m4-2-2-2-absorption>
<m4-2-2-3-distribution>
<leaf>
</leaf>
</m4-2-2-3-distribution>
<m4-2-2-4-metabolism>
<leaf>
</leaf>
</m4-2-2-4-metabolism>
24
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
4.2.3.3.2 In vivo
End Genotoxicity
4.2.3.4 Carcinogenicity
4.2.3.4.1 Long-term studies
Version 1.1
eCTD Element
<m4-2-2-5-excretion>
<leaf>
</leaf>
</m4-2-2-5-excretion>
<m4-2-2-6-pharmacokinetic-drug-interactions>
<leaf>
</leaf>
</m4-2-2-6-pharmacokinetic-drug-interactions>
<m4-2-2-7-other-pharmacokinetic-studies>
<leaf>
</leaf>
</m4-2-2-7-other-pharmacokinetic-studies>
</m4-2-2-pharmacokinetics>
<m4-2-3-toxicology>
<m4-2-3-1-single-dose-toxicity>
<leaf>
</leaf>
</m4-2-3-1-single-dose-toxicity>
<m4-2-3-2-repeat-dose-toxicity>
<leaf>
</leaf>
</m4-2-3-2-repeat-dose-toxicity>
<m4-2-3-3-genotoxicity>
<leaf>
</leaf>
<m4-2-3-3-1-in-vitro>
<leaf>
</leaf>
</m4-2-3-3-1-in-vitro>
<m4-2-3-3-2-in-vivo>
<leaf>
</leaf>
</m4-2-3-3-2-in-vivo>
</m4-2-3-3-genotoxicity>
<m4-2-3-4-carcinogenicity>
<m4-2-3-4-1-long-term-studies>
<leaf>
</leaf>
</m4-2-3-4-1-long-term-studies>
<m4-2-3-4-2-short-or-medium-term-studies>
<leaf>
</leaf>
</m4-2-3-4-2-short-or-medium-term-studies>
25
End Carcinogenicity
4.2.3.5 Reproductive and
Developmental Toxicity
4.2.3.5.1 Fertility and early
embryonic development
4.2.3.5.2 Embryofetal
development
4.2.3.5.3 Prenatal and postnatal
development, including maternal
function
Version 1.1
eCTD Element
<m4-2-3-4-3-other-studies>
<leaf>
</leaf>
</m4-2-3-4-3-other-studies>
</m4-2-3-4-carcinogenicity>
<m4-2-3-5-reproductive-and-developmentaltoxicity>
<m4-2-3-5-1-fertility-and-early-embryonicdevelopment>
<leaf>
</leaf>
</m4-2-3-5-1-fertility-and-early-embryonicdevelopment>
<m4-2-3-5-2-embryo-fetal-development>
<leaf>
</leaf>
</m4-2-3-5-2-embryo-fetal-development>
<m4-2-3-5-3-prenatal-and-postnataldevelopment-including-maternal-function>
<leaf>
</leaf>
</m4-2-3-5-3-prenatal-and-postnataldevelopment-including-maternal-function>
<m4-2-3-5-4-studies-in-which-the-offspringjuvenile-animals-are-dosed-and-or-furtherevaluated>
<leaf>
</leaf>
</m4-2-3-5-4-studies-in-which-the-offspringjuvenile-animals-are-dosed-and-or-furtherevaluated>
</m4-2-3-5-reproductive-and-developmentaltoxicity>
<m4-2-3-6-local-tolerance>
<leaf>
</leaf>
</m4-2-3-6-local-tolerance>
<m4-2-3-7-other-toxicity-studies>
<m4-2-3-7-1-antigenicity>
<leaf>
</leaf>
</m4-2-3-7-1-antigenicity>
26
4.2.3.7.4 Dependence
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 Other
End Other
End Toxicology
End Study Reports
4.3 Literature References
End Nonclinical
eCTD Element
<m4-2-3-7-2-immunotoxicity>
<leaf>
</leaf>
</m4-2-3-7-2-immunotoxicity>
<m4-2-3-7-3-mechanistic-studies>
<leaf>
</leaf>
</m4-2-3-7-3-mechanistic-studies>
<m4-2-3-7-4-dependence>
<leaf>
</leaf>
</m4-2-3-7-4-dependence>
<m4-2-3-7-5-metabolites>
<leaf>
</leaf>
</m4-2-3-7-5-metabolites>
<m4-2-3-7-6-impurities>
<leaf>
</leaf>
</m4-2-3-7-6-impurities>
<m4-2-3-7-7-other>
<leaf>
</leaf>
</m4-2-3-7-7-other>
</m4-2-3-7-other-toxicity-studies>
</m4-2-3-toxicology>
</m4-2-study-reports>
<m4-3-literature-references>
<leaf>
</leaf>
</m4-3-literature-references>
</m4-nonclinical-study-reports>
An example of the elements used to organize the leaf element for the Embryo Fetal Development
Toxicology heading document is provided:
<m4-nonclinical-study-reports>
<m4-2-study-reports>
<m4-2-3-toxicology>
<m4-2-3-5-reproductive-and-developmental-toxicity>
<m4-2-3-5-2-embryo-fetal-development>
<leaf></leaf>21
</m4-2-3-5-2-embryo-fetal-development>
21
Version 1.1
27
Version 1.1
eCTD Element
<m5-clinical-study-reports>
<m5-2-tabular-listing-of-all-clinical-studies>
<leaf>
</leaf>
</m5-2-tabular-listing-of-all-clinical-studies>
<m5-3-clinical-study-reports>
<m5-3-1-reports-of-biopharmaceutic-studies >
<m5-3-1-1-bioavailability-study-reports>
<leaf>
</leaf>
</m5-3-1-1-bioavailability-study-reports>
28
End Biopharm
5.3.2 Reports Of Studies Pertinent To
Pharmacokinetics Using Human
Biomaterials
5.3.2.1 Plasma Protein Binding Study
Reports
5.3.2.2 Reports Of Hepatic
Metabolism And Drug Interaction
Studies
Version 1.1
eCTD Element
<m5-3-1-2-comparative-ba-and-bioequivalencestudy-reports>
<leaf>
</leaf>
</m5-3-1-2-comparative-ba-and-bioequivalencestudy-reports>
<m5-3-1-3-in-vitro-in-vivo-correlation-studyreports>
<leaf>
</leaf>
</m5-3-1-3-in-vitro-in-vivo-correlation-studyreports>
<m5-3-1-4-reports-of-bioanalytical-and-analyticalmethods-for-human-studies>
<leaf>
</leaf>
</m5-3-1-4-reports-of-bioanalytical-and-analyticalmethods-for-human-studies>
</m5-3-1-reports-of-biopharmaceutic-studies>
<m5-3-2-reports-of-studies-pertinent-topharmacokinetics-using-human-biomaterials>
<m5-3-2-1-plasma-protein-binding-study-reports>
<leaf>
</leaf>
</m5-3-2-1-plasma-protein-binding-study-reports>
<m5-3-2-2-reports-of-hepatic-metabolism-and-druginteraction-studies>
<leaf>
</leaf>
</m5-3-2-2-reports-of-hepatic-metabolism-anddrug-interaction-studies>
<m5-3-2-3-reports-of-studies-using-other-humanbiomaterials>
<leaf>
</leaf>
</m5-3-2-3-reports-of-studies-using-other-humanbiomaterials>
</m5-3-2-reports-of-studies-pertinent-topharmacokinetics-using-human-biomaterials>
<m5-3-3-reports-of-human-pharmacokinetics-pkstudies>
29
End PK
5.3.4 Reports Of Human
Pharmacodynamic (PD) Studies
5.3.4.1 Healthy Subject PD And
PK/PD Study Reports
22
eCTD Element
<m5-3-3-1-healthy-subject-pk-and-initialtolerability-study-reports>
<leaf>
</leaf>
</m5-3-3-1-healthy-subject-pk-and-initialtolerability-study-reports>
<m5-3-3-2-patient-pk-and-initial-tolerability-studyreports>
<leaf>
</leaf>
</m5-3-3-2-patient-pk-and-initial-tolerability-studyreports>
<m5-3-3-3-intrinsic-factor-pk-study-reports>
<leaf>
</leaf>
</m5-3-3-3-intrinsic-factor-pk-study-reports>
<m5-3-3-4-extrinsic-factor-pk-study-reports>
<leaf>
</leaf>
</m5-3-3-4-extrinsic-factor-pk-study-reports>
<m5-3-3-5-population-pk-study-reports>
<leaf>
</leaf>
</m5-3-3-5-population-pk-study-reports>
</m5-3-3-reports-of-human-pharmacokinetics-pkstudies>
<m5-3-4-reports-of-human-pharmacodynamics-pdstudies>
<m5-3-4-1-healthy-subject-pd-and-pk-pd-studyreports>
<leaf>
</leaf>
</m5-3-4-1-healthy-subject-pd-and-pk-pd-studyreports>
<m5-3-4-2-patient-pd-and-pk-pd-study-reports>
<leaf>
</leaf>
</m5-3-4-2-patient-pd-and-pk-pd-study-reports>
</m5-3-4-reports-of-human-pharmacodynamics-pdstudies>
<m5-3-5-reports-of-efficacy-and-safety-studies
indication="">22
Version 1.1
30
End Module 5
eCTD Element
<m5-3-5-1-study-reports-of-controlled-clinicalstudies-pertinent-to-the-claimed-indication>
<leaf>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinicalstudies-pertinent-to-the-claimed-indication>
<m5-3-5-2-study-reports-of-uncontrolled-clinicalstudies>
<leaf>
</leaf>
</m5-3-5-2-study-reports-of-uncontrolled-clinicalstudies>
<m5-3-5-3-reports-of-analyses-of-data-from-morethan-one-study>
<leaf>
</leaf>
</m5-3-5-3-reports-of-analyses-of-data-from-morethan-one-study>
<m5-3-5-4-other-study-reports>
<leaf>
</leaf>
</m5-3-5-4-other-study-reports>
</m5-3-5-reports-of-efficacy-and-safety-studies>
<m5-3-6-reports-of-postmarketing-experience>
<leaf>
</leaf>
</m5-3-6-reports-of-postmarketing-experience>
This heading is not used. The leaf for case report forms
and individual patient listings files are placed with the
appropriate study report using the Study Tagging File
<m5-4-literature-references>
<leaf>
</leaf>
</m5-4-literature-references>
<m5-clinical-study-reports>
Version 1.1
31
23
24
Version 1.1
32
SECTION 10
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.
Page 1
Page 5
The following is an example of the use of the study-identifier elements in an STF for a
long term carcinogenicity study conducted in mice (species="mouse"):
<study-identifier>
<title>Long term carcinogenicity study</title>
<study-id>abc123xyz789</study-id>
<category name="species" info-type="ich" >mouse</category>
<category name="duration" info-type="us" >long</category>
</study-identifier>
III. STUDY-DOCUMENT AND DOC-CONTENT ELEMENTS
The study-document element2 contains information on the subject matter of each file that
is cited as part of the documentation for a study. The study-document element includes
the doc-content element. The doc-content element contains the property and file-tag
elements.
A. Property element
The property element is appropriate when files might need to be grouped by an applicant
provided value. Currently, this element is only to be used for site identification within a
study. For example, in the submission of case-report-forms, multiple forms originating
from the same study site should all be grouped by the study site property element.
Property Element
Attributes and Values
name="site-identifier"
info-type="us"
B. File-tag element
The file-tag element contains the attributes name and info-type. The text value of the filetag element's name attribute indicates the subject matter of the document. The value of
the file-tag name attribute should be selected from the values in the table below. For the
value of the info-type attribute, you should use "ich" if using an ICH value or one of the
The ICH STF Specification v2.6 includes a second element named block-content. However STF files
submitted to FDA should not utilize the block-content construct.
Page 6
infotype
value
ich
legacy-clinical-studyreport
synopsis
study-report-body
protocol-or-amendment
sample-case-report-form
iec-irb-consent-form-list
ich
list-descriptioninvestigator-site
ich
signatures-investigators
ich
list-patients-withbatches
ich
randomisation-scheme
audit-certificates-report
ich
ich
statistical-methodsinterim-analysis-plan
inter-laboratorystandardisationmethods-qualityassurance
ich
ich
ich
ich
ich
ich
ich
Content of Document
Pre-clinical study report ( 3see footnote)
NOTE: Do not use in STF submitted
to FDA4
Clinical study report submitted as one
file (*see footnote)
Study Report Synopsis
Study Report Body
Protocol and/amendments
Sample CRF
IEC and IRB and Consent Form
Listings
Description of Investigators and Sites
Signatures of principal or coordinating
investigator(s) or sponsors responsible
officer
Listing of patients receiving test
drug(s) from specified batch
Randomisation Scheme
Audit Certificates or similar
documentation
Documentation of statistical methods
and interim analysis plans
Documentation of Inter-laboratory
Standardization Methods and Quality
Assurance or similar documentation
E3
Reference
2
1,3 to 15
16.1.1
16.1.2
16.1.3
16.1.4
16.1.5
16.1.6
16.1.7
16.1.8
16.1.9
16.1.10
Refer to M4: Organisation Document, Granularity Annex for instructions on how to typically construct
study reports.
4
FDA does not use this STF tag value use the US specific "nonclinical-data" tag instead
Page 7
infotype
value
ich
publications-referencedin-report
discontinued-patients
protocol-deviations
ich
ich
ich
patients-excluded-fromefficacy-analysis
demographic-data
compliance-and-drugconcentration-data
individual-efficacyresponse-data
adverse-event-listings
listing-individuallaboratorymeasurements-bypatient
case-report-forms
ich
available-on-request
ich
complete-patient-list
jp
serious-adverse-eventpatient-list
jp
adverse-event-patientlist
jp
abnormal-lab-valuespatient-list
jp
data-tabulation-dataset
us
ich
ich
ich
ich
ich
ich
Content of Document
Publications Based on the Study
Publications Referenced in the Study
Report
Discontinued Patients Listing
Protocol Deviation Listing
Patients Excluded from Efficacy
Analysis Listing
Demographic Data Listing
Compliance and/or Drug Concentration
Data Listing
Individual Efficacy Response Data
Listing
File contains Adverse Event Listings
Individual Laboratory Measurements
Listed by Patient
CRF for an individual subject. If you
are submitting in the US, you should
also provide a "property" element,
described below, with its "name"
attribute = "site-identifier" and its value
the site identification where the study
was performed.
A file listing documents available upon
request for a single study. Consult
regional guidance for use.
Complete patient list (Not used in STF
files submitted to FDA)
List of patients having serious adverse
events (Not used in STF files
submitted to FDA)
List of patients having adverse events
(Not used in STF files submitted to
FDA)
List of patients having abnormal lab
values (Not used in STF files submitted
to FDA)
Data tabulation dataset
E3
Reference
16.1.11
16.1.12
16.2.1
16.2.2
16.2.3
16.2.4
16.2.5
16.2.6
16.2.7
16.2.8
16.3
Page 8
us
us
us
us
us
us
us
safety-report
antibacterial
special-pathogen
us
us
us
antiviral
iss
us
us
ise
us
pm-description
us
individual-subject-datalisting
nonclinical-data
us
us
us
Content of Document
E3
Reference
us
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
If there was no additional documentation being provided for this study (and thus the
purpose of this STF is solely to correct the erroneous study-identifier information), the
STF would contain the following:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../util/style/ich-stf-stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Single dose oral toxicity study in the mouse and dog</title>
<study-id>jm-12-345</study-id>
<category name="species" info-type="ich">mouse</category>
<category name="species" info-type="ich">dog</category>
<category name="route-of-admin" info-type="ich">oral</category>
</study-identifier>
<study-document/>
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.
Note: The entire study-identifier block should be resubmitted containing all the category
values. The <study-document/> indicates that no additional file-tags are being provided and
is required since the study-document element is a mandatory element.
Page 14
Then, add the file as "new" citing the location in the 0000 serial submission - there is no
need to send a second copy of the file:
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="../0000/m4/42-stud-rep/423-tox/4231-single-dose-tox/synopsis-of-jm-12345.pdf"
application-version="PDF 1.3"
<title>jm-12-345 Study Synopsis</title>
ID="r34567">
</leaf>
Page 15
Finally, include a new STF (using the "append" operation) and associate the correct
synopsis file-tag to the file.
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="append"
xlink:href="m4/42-stud-rep/423-tox/4231-single-dose-tox/stf-jm-12-345.xml"
modified-file="../0000/index.xml#m42112"
ID="r6789">
<title>Study JM-12-345 STF</title>
</leaf>
In the serial 0003 STF for JM-12-345, include the study-id tag to identify the study
report being modified and include the corrected file-tag metadata:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Single dose oral toxicity study in the mouse and dog</title>
<study-id>jm-12-345</study-id>
<category name="species" info-type="ich">mouse</category>
<category name="species" info-type="ich">dog</category>
<category name="route-of-admin" info-type="ich">oral</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../index.xml#r34567">
<file-tag name="synopsis" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Page 16
Page 18
The STF provided in submission 0000 is named "stf-s107.xml" and contains the
following information about the documentation being provided for study S107:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet-2-2.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Wonderdrug Study S107</title>
<study-id>S107</study-id>
<category name="type-of-control" info-type="ich">no-treatment</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#a101">
<file-tag name="synopsis" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#a102">
<file-tag name="study-report-body" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#a103">
<file-tag name="protocol-or-amendment info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.
Note: The type of control for this study was intentionally cited as no-treatment even
though the study is a placebo-controlled study. This will be corrected in a subsequent
submission (see submission 0002).
Page 19
Submission 0001
In a subsequent submission, the sponsor wishes to provide additional documentation on
Study S107. In submission 0001, the Sponsor provides the Sample Case Report Form and
a protocol amendment.
The index.xml for submission 0001 would contain three leaf entries; one for each content
file (i.e., the protocol amendment and the Sample CRD) and one for the STF. The leaf
entries for the new content files would be identical whether the Sponsor chooses to use
the Cumulative or Accumulative approaches. The leaf entry for the STF and the content
of the STF would differ depending on which approach was utilized.
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
The index.xml for submission 0001 would contain three leaf entries; one for each content
file (i.e., the protocol amendment and the Sample CRD) and one for the STF which
updates the previously submitted STF as shown here:
<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimedindication>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="421e55366d62fad0e9510f6aed005272" operation="new"
xlink:href="m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/protamend01.pdf"
application-version="PDF 1.3"
ID="a567">
<title>S107 Protocol Amendment No. 1</title>
</leaf>
<leaf checksum-type="MD5"
version=" " xlink:type="simple"
checksum="88e3be3f2d026b572625ab81ef5b068c" operation="new"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/samplecrf.pdf"
application-version="PDF 1.3"
ID="a568">
<title>S107 Sample Case Report Form</title>
</leaf>
<leaf checksum-type="MD5"
version="STF Version 2.2" xlink:type="simple"
checksum="25d3b246313a9dbf688a48da2295260e" operation="append"
xlink:href=" m5/53-clin-stud-rep/535-rep-effic-safety-stud/nausea/5351-stud-repcontr/study-s107/stf-s107.xml"
modified-file="../0000/index.xml#a104"
ID="a569">
Page 20
The new STF is also named "stf-s107.xml" and summarizes only the new information
being provided in this submission as follows:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-2-2stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Wonderdrug Study S107</title>
<study-id>S107</study-id>
<category name="type-of-control" info-type="ich">no-treatment</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#a567">
<file-tag name="protocol-or-amendment" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#a568">
<file-tag name="sample-case-report-form" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.
Submission 0002
In a subsequent submission, the sponsor wishes to provide additional documentation on
Study S107. In submission 0002, the Sponsor provides the final study report and synopsis
plus CRF files for two patients who died during the conduct of the study. In addition, it
was finally noticed that the previous STFs had incorrectly identified the study as an
uncontrolled study when, in fact, it was placebo-controlled.
Cumulative Approach
FDA does not use the Cumulative Approach for Study Tagging Files.
Accumulative Approach
The index.xml for submission 0002 would contain five leaf entries; one for each content
file (i.e., synopsis, study report and two patient CRF files) and one for the STF which
would append the previously submitted STF as shown here:
Page 21
Page 22
The new STF is named "stf-s107.xml" and identifies the additional documentation
provided for Study S107 in this submission. The information in this STF also corrects the
erroneous type-of-control category tag to placebo as follows:
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl" href="../../../../util/style/ich-stf-stylesheet-2-2.xsl"?>
<!DOCTYPE ectd:study SYSTEM "../../../../util/dtd/ich-stf-v2-2.dtd">
<ectd:study xmlns:ectd="http://www.ich.org/ectd" xml:lang="en" dtd-version="2.2"
xmlns:xlink="http://www.w3.org/1999/xlink">
<study-identifier>
<title>Wonderdrug Study S107</title>
<study-id>S107</study-id>
<category name="type-of-control" info-type="ich">placebo</category>
</study-identifier>
<study-document>
<doc-content xlink:href="../../../../../index.xml#r345">
<file-tag name="synopsis" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r346">
<file-tag name="study-report-body" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r347" >
<property name="site-identifier" info-type="us">11</property>
<file-tag name="case-report-forms" info-type="ich"/>
</doc-content>
<doc-content xlink:href="../../../../../index.xml#r348" >
<property name="site-identifier" info-type="us">162</property>
<file-tag name="case-report-forms" info-type="ich"/>
</doc-content>
</study-document>
</ectd:study>
Note: "../../../../" in the path expressions for STF DTD and STF stylesheet depend on the
location where the STF instance is stored.
Page 23
SECTION 11
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.
Version
Number
Version 1.0
Version 1.1
December 2002
Version 1.2
Version 1.3
January 2003
January 2003
Version 1.4
Version 1.5
Version 1.6
Version 1.7
February 2003
July 15, 2003
July 17, 2003
July 18, 2003
Version 1.8
Description
Initial Baseline
Teleconference review of required
section
Revised by subsection of M2 EWG
Comments from subset of M2
members
ICH Tokyo M2 Meeting
ICH Brussels M2 Meeting
ICH Brussels M2 Meeting
ICH Brussels M2 Meeting FDA
Lawyer Comments
ICH Tysons Corner Meeting Add
release schedules
Introduction
At the September 2002 ICH Steering Committee meeting, the ICH M2 Expert Working
Group (EWG) presented the signed Step 3 eCTD Specification for Step 4 consideration
by the ICH Steering Committee. The Steering Committee signed the specification to Step
4 and tasked the M2 EWG to also be the Implementation Working Group (IWG) for the
eCTD Specification. To implement the eCTD across all three regions, change control
should be in place to effectively communicate and execute changes to the eCTD
Specification.
Scope
This document establishes the change control process for the eCTD Specification.
Change control for regional eCTD Module 1 specifications is the regional authoritys
responsibility.
Purpose
The eCTD IWG is authorised by the ICH Steering Committee to administer changes to
the eCTD Specification. Change control is established to serve the following purposes:
Evaluate and approve or disapprove proposed changes to the eCTD Specification
Ensure implementation of approved changes
Represent the interests of all groups who might be affected by changes
Members
The eCTD IWG consists of a Topic Leader, Deputy Topic Leader, and Experts from each
of the six ICH parties, and ICH observers. The Steering Committee can also nominate, or
the eCTD IWG can request, additional members to work with the eCTD IWG to support
eCTD change control.
These members of the eCTD IWG are responsible for performing functions related to
eCTD change control.
Rapporteur
The eCTD IWG Rapporteur will be responsible for:
Organising and presenting change requests to eCTD IWG in RTF format
Presenting results of eCTD change control meetings to ICH Steering Committee
Ensuring results of change control meetings are posted on the ICH Web site
(www.ich.org)
Identifying change requests in the eCTD Q&A document
Topic Leaders/Deputy Topic Leaders
The Topic Leaders for ICH parties will be responsible for:
Submitting their partys vote on eCTD change control
Assigning regional members to present change requests originating in their region as
needed
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.
SECTION 12
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.
Contact Information
Organisation Name:
Organisation
Address:
Contact Name:
Address:
Telephone Number:
E-mail Address:
Submit Date
Item to be
Changed/ Question
Version Number
and Date
Description
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
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 M2 EWG
Electronic Common Technical Document Specification
Date
Version 3.0
Version 3.1
October 2003
November 2003
Version 3.2
February 2004
Description
Background
The specification for the eCTD is based upon content defined within the CTD issued by the ICH M4 EWG.
The CTD describes the organization of modules, sections and documents. The structure and level of detail
specified in the CTD have been used as the basis for defining the eCTD structure and content but where
appropriate, additional details have been developed within the eCTD specification.
The philosophy of the eCTD is to use open standards. Open standards, including proprietary standards,
which through their widespread use can be considered de facto standards, are deemed to be appropriate in
general.
Scope
The CTD as defined by the M4 EWG does not cover the full submission that is to be made in a region. It
describes only modules 2 to 5, which are common across all regions. The CTD does not describe the
content of module 1, the Regional Administrative Information and Prescribing Information, nor does it
describe documents that can be submitted as amendments or variations to the initial application.
The value of producing a specification for the creation of an electronic submission based only upon the
modules described in the CTD would be limited. Therefore, the M2 EWG has produced a specification for
the eCTD that is applicable to all modules of initial registration applications and for other submissions of
information throughout the lifecycle of the product, such as variations and amendments.
This document describes the parts of the registration application that are common to all regions and some
of the lifecycle requirements for products. The parts of the registration application that are specific to a
region will be covered by regional guidance. However, this backbone has been developed to handle both
the regional and common parts of submissions.
Requirements
The specification is designed to support high-level functional requirements such as the following:
Page 1
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
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.
Page 1-1
Lifecycle Management
The applicant creates a submission that is stored in a local repository. The applicant submits the initial
submission to the agency, which imports the submission into another local repository. The nature and kind
of the local repositories is not within the scope of the eCTD. The initial submission should be selfcontained meaning that it includes all documents and no references to other submissions. Regional
guidance should be consulted if references to other submissions are needed.
Following the initial submission, the applicant can submit incremental updates such as amendments and
variations. Updates can refer to documents in the previous submissions. Updates should be designed in a
way that they can be loaded into the repository by fully preserving the initial or previous submission via
version control. The XML backbone should include meta-data identifying the update and providing
navigation aids to filter for different submission types.
It is preferred that when a Common Technical Document is submitted electronically, the entire submission
should be in electronic form with the exception of certain regional forms that currently require written
signatures. See appendix 5 for regional requirements. See appendix 6 for a description of how to submit a
CTD containing both paper and electronic components.
Page 1-2
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.
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.
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.
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.
Page 2-3
File Extension
All files should have one and only one file extension. The file extension should be used to indicate the
format of the file. For example:
hello.pdf
hello.rtf
PDF
RTF
css
html or htm
xml
pdf
rtf
xls
jpg
png
gif
dtd
xpt
xsl
The eCTD submission could use formats not registered with the Internet Assigned Numbers Authority
(IANA).
The presence of a format in this list does not imply that it would be considered an acceptable format. For
formats absent from this list, widely used mapping between the formats and the extensions should be used.
Future direction: if a mechanism (e.g., standard) becomes available that associates the formats with file
extension; it should be considered for this specification.
Name
Name is a token composed of the following characters:
Letters "a" to "z" [U+0061 to U+007A].
Digits "0" to "9" [U+0030 to U+0039].
"-" [HYPHEN-MINUS, U+002D].
The notation "U+" refers to the Unicode [UNICODE] notation.
Page 2-4
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
Page 2-6
File Name
Study Report 1
study-report-1.pdf
Study Report 2
study-report-2.pdf
Study Report n
study-report-n.pdf
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 2 Summaries
The files in this module should be provided as PDF text with the exception of a few embedded images,
when needed. The name of the folder for module 2 should be m2. The folders in module 2 should be named
as follows.
Table 3-2
Section in
CTD
Description
Folder Name
2.2
Introduction
22-intro
2.3
23-qos
2.4
Nonclinical Overview
24-nonclin-over
2.5
Clinical Overview
25-clin-over
2.6
26-nonclin-sum
2.7
Clinical summary
27-clin-sum
The folder hierarchy for module 2 is presented in the screenshot in figure 3-1.
Figure 3-1 Screenshot of the folder structure of module 2
Module 3 Quality
The name of the folder for module 3 should be m3. The folders in module 3 should be named as follows.
Table 3-3
Section in
CTD
Page 3-2
Description
Folder Name
Section in
CTD
Description
Folder Name
3.2
Body of Data
32-body-data
3.2.S
Drug Substance
32s-drug-sub
3.2.S
substance-1-manufacturer-1
3.2.S.1
32s1-gen-info
3.2.S.2
32s2-manuf
3.2.S.3
32s3-charac
3.2.S.4
32s4-contr-drug-sub
3.2.S.4.1
3.2.S.4.2
32s42- analyt-proc
3.2.S.4.3
32s43-val-analyt-proc
3.2.S.4.4
3.2.S.4.5
32s41-spec
32s44-batch-analys
3.2.S.7
3.2.P
32p-drug-prod
3.2.P
product-1
3.2.P.1
32p1-desc-comp
3.2.P.3
3.2.P.4
32p4-contr-excip
3.2.P.4
excipient-1
3.2.S.5
3.2.S.6
3.2.P.2
3.2.P.5
2
32s45-justif-spec
32s5-ref-stand
32s6-cont-closure-sys
32s7-stab
32p2-pharm-dev
32p3-manuf
32p5-contr-drug-prod
Each drug substance-manufacturer should be placed in a separate subordinate folder. Folders and files
should be created for each drug substance-manufacturer section included in the submission in accordance
with the hierarchy identified in the following chapters.
3
Each drug product should be placed in a separate subordinate folder. Folders and files should be created
for each drug product section included in the submission in accordance with the hierarchy identified in the
following chapters. Reference should be made to regional guidance to determine whether the inclusion of
multiple products within a single application is considered appropriate.
Page 3-3
Section in
CTD
Description
Folder Name
3.2.P.5.1
32p51-spec
3.2.P.5.2
32p52-analyt-proc
3.2.P.5.3
32p53-val-analyt-proc
3.2.P.5.4
3.2.P.5.5
32p54-batch-analys
32p55-charac-imp
3.2.P.7
3.2.P.8
32p8-stab
3.2.A
Appendices
32a-app
3.2.A.1
32a1-fac-equip
3.2.A.2
32a2-advent-agent
3.2.A.3
3.2.R
Regional Information5
32r-reg-info
3.3
Literature References
33-lit-ref
3.2.P.5.6
3.2.P.6
32p56-justif-spec
32p6-ref-stand
32p7-cont-closure-sys
32a3-excip-name-1
The folder name should include the name of the excipient, abbreviated as necessary to remain within the
64 character limit.
5
This folder should be included where regional information is appropriate. Reference should be made to
regional guidance for the types of information to be included in this section.
Page 3-4
The folder hierarchy for module 3 is presented in the screenshot in figure 3-2.
Figure 3-2 Screenshot of the folder structure of module 3
Page 3-5
Description
Study Reports
Folder Name
42-stud-rep
Section in
CTD
Description
Folder Name
4.2.1
Pharmacology
421-pharmacol
4.2.1.1
Primary Pharmacodynamics
4211-prim-pd
4.2.1.2
Secondary Pharmacodynamics
4212-sec-pd
4.2.1.3
Safety Pharmacology
4213-safety-pharmacol
4.2.1.4
4214-pd-drug-interact
4.2.2
Pharmacokinetics
422-pk
4.2.2.1
4221-analyt-met-val
4.2.2.2
Absorption
4222-absorp
4.2.2.3
Distribution
4223-distrib
4.2.2.4
Metabolism
4224-metab
4.2.2.5
Excretion
4225-excr
4.2.2.6
4226-pk-drug-interact
4.2.2.7
4227-other-pk-stud
4.2.3
Toxicology
423-tox
4.2.3.1
4231-single-dose-tox
4.2.3.2
4232-repeat-dose-tox
4.2.3.3
Genotoxicity
4233-genotox
4.2.3.3.1
In vitro
42331-in-vitro
4.2.3.3.2
42332-in-vivo
4.2.3.4
4234-carcigen
4.2.3.4.1
42341-lt-stud
4.2.3.4.2
42342-smt-stud
Page 3-6
Section in
CTD
Description
Folder Name
4.2.3.4.3
Other studies
42343-other-stud
4.2.3.5
4235-repro-dev-tox
4.2.3.5.1
42351-fert-embryo-dev
4.2.3.5.2
Embryo-fetal development
42352-embryo-fetal-dev
4.2.3.5.3
42353-pre-postnatal-dev
4.2.3.5.4
42354-juv
4.2.3.6
Local Tolerance
4236-loc-tol
4.2.3.7
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
42373-mechan-stud
4.2.3.7.4
Dependence
42374-dep
4.2.3.7.5
Metabolites
42375-metab
4.2.3.7.6
Impurities
42376-imp
4.2.3.7.7
Other
42377-other
4.3
Literature References
43-lit-ref
The folder hierarchy for module 4 is presented in the screenshot in figure 3-3.
Page 3-7
Page 3-8
Description
Tabular Listing of all Clinical Studies
Folder Name
52-tab-list
Section in
CTD
Description
Folder Name
5.3
53-clin-stud-rep
5.3.1
531-rep-biopharm-stud
5.3.1.1
5311-ba-stud-rep
study-report-1
study-report-2
study-report-3
5312-compar-ba-be-stud-rep
study-report-1
study-report-2
study-report-3
5313-in-vitro-in-vivo-corr-stud-rep
study-report-1
study-report-2
study-report-3
5314-bioanalyt-analyt-met
study-report-1
study-report-2
study-report-3
5.3.2
532-rep-stud-pk-human-biomat
5.3.2.1
5321-plasma-prot-bind-stud-rep
study-report-1
study-report-2
study-report-3
5322-rep-hep-metab-interact-stud
study-report-1
study-report-2
5.3.1.2
5.3.1.3
5.3.1.4
5.3.2.2
Page 3-9
Section in
CTD
Description
Folder Name
study-report-3
5323-stud-other-human-biomat
study-report-1
study-report-2
study-report-3
5.3.3
533-rep-human-pk-stud
5.3.3.1
5331-healthy-subj-pk-init-tol-stud-rep
study-report-1
study-report-2
study-report-3
5332-patient-pk-init-tol-stud-rep
study-report-1
study-report-2
study-report-3
5333-intrin-factor-pk-stud-rep
study-report-1
study-report-2
study-report-3
5334-extrin-factor-pk-stud-rep
study-report-1
study-report-2
study-report-3
5335-popul-pk-stud-rep
study-report-1
study-report-2
study-report-3
5.3.2.3
5.3.3.2
5.3.3.3
5.3.3.4
5.3.3.5
Page 3-10
Section in
CTD
Description
Folder Name
5.3.4
534-rep-human-pd-stud
5.3.4.1
5341-healthy-subj-pd-stud-rep
study-report-1
study-report-2
study-report-3
5342-patient-pd-stud-rep
study-report-1
study-report-2
study-report-3
5.3.4.2
535-rep-effic-safety-stud
5.3.5
5.3.5
indication-1
5.3.5.1
5351-stud-rep-contr
study-report-1
study-report-2
study-report-3
5352-stud-rep-uncontr
study-report-1
study-report-2
study-report-3
5353-rep-analys-data-more-one-stud
study-report-1
study-report-2
study-report-3
5354-other-stud-rep
study-report-1
5.3.5.2
5.3.5.3
5.3.5.4
Page 3-11
Section in
CTD
Description
Folder Name
study-report-2
study-report-3
5.3.6
536-postmark-exp
5.3.7
537-crf-ipl
Study Report 1
study-report-1
Study Report 2
study-report-2
Study Report 3
study-report-3
Literature References
54-lit-ref
5.4
This folder contains as many folders as studies are included that have included case report forms and/or
individual patient listings. The folders should be named like the corresponding study. The content of the
folders should follow regional guidance.
Page 3-12
The folder hierarchy for module 5 is presented in the screenshot in figure 3-4.
Figure 3-4 Screenshot of the folder structure of module 5
Page 3-13
Page 3-14
Page 3-15
Comment
Number
Title
Element
File/Directory
Each item in the table has a unique sequentially assigned reference number. These reference numbers can
change with each version of this appendix.
CTD section number
CTD title
Element name in the Backbone
Relative path of the File/Directory. The file extension corresponds to the file type; i.e., the pdf extension is
only illustrative. Refer to Table 6.1, Appendix 6, for details for the head of the path name
Comments
Page 4-1
Where file names are presented in italics applicants would substitute these with file names in accordance with their own naming conventions.
The file organization table covers files that constitute the backbone itself plus necessary additional files to make the submission complete, readable and
processable. The file names are not mandatory, but highly recommended. Refer to the M4 Organisation Document: Granularity Annex for information on where
multiple documents/files are allowed in each section or subsection of the eCTD.
Sequential
number
Each item in the file organization table that is listed in this appendix includes the information outlined below:
Page 4-2
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
index-md5.txt
The MD5 of the Backbone
index.xml
This is the Backbone
Table 4-1
1
Administrative Information and Prescribing Information
m1-administrative-information-and-prescribing-information
m1
Only one of the regional directories is needed
Page 4-3
m1/eu
EU directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to regional
Comment
guidance for details
Number
Title
Element
Directory m1/jp
Japan directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to
Comment
regional guidance for details
Number
Title
Element
Directory m1/us
US directory: In addition to the appropriate regional documents, the regional xml instance should be located in this folder. Refer to regional
Comment
guidance for details
Number
Title
Element
Directory m1/xx
xx directory; where xx is a two character country code from ISO-3166-1. In addition to the appropriate regional documents, the regional
Comment
xml instance should be located in this folder. Refer to regional guidance for details
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
2.2
Introduction
m2-2-introduction
m2/22-intro/introduction.pdf
2.2
Introduction
m2-2-introduction
m2/22-intro
2
Common Technical Document Summaries
m2-common-technical-document-summaries
m2
Page 4-4
2.3
Quality Overall Summary
m2-3-quality-overall-summary
m2/23-qos
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Comment
Overall Summary
Number
2.3
Title
Introduction
12 Element
m2-3-introduction
File
m2/23-qos/introduction.pdf
Comment
13 Number
2.3.S
Title
Drug Substance - Name - Manufacturer
Element
m2-3-s-drug-substance
File
m2/23-qos/drug-substance.pdf
Number
Title
8 Element
Directory
Comment
Number
Title
9 Element
Directory
Comment
Number
Title
10 Element
File
Comment
Number
Title
Element
11
Directory
Page 4-5
2.3.P
Drug Product -Name
m2-3-p-drug-product
m2/23-qos/drug-product-name.pdf
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Overall Summary
14
he file name should always include the name of the drug product through inclusion of the name of the form/strength to give e.g., 'drugproduct-tablet-5mg'.
Comment
Where the application is for a complex presentation with multiple components the file name should identify additional items such as the
component.
Refer to regional guidance for definition of what constitutes a drug product and the acceptability of more than one drug product in an
application. Where more than one drug product is acceptable in an application, a separate file should be provided for each drug product.
Number
2.3.A
Title
Appendices
Element
m2-3-a-appendices
15
File
m2/23-qos/appendices.pdf
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Comment
Overall Summary
Number
2.3.R
Title
Regional Information
Element
m2-3-r-regional-information
16
File
m2/23-qos/regional-information.pdf
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the Quality
Comment
Overall Summary
17 Number
2.4
Number
Title
Element
File
Where there are more than one drug substance and/or manufacturer, separate files should be provided for each. The
file name should always include the name of the drug substance e.g., ranitidine hydrochloride through inclusion of
Comment the International Non-proprietary Name to give 'ranitidine-hydrochloride'. Similarly, for manufacturer, the file name
should always include the name of the manufacturer e.g., ranitidine-hydrochloride-manufacturer-1.pdf.
Where there is more than one manufacturer, the drug substance file should be repeated but with an indication of
each manufacturer concerned included in the file name, the first instance e.g., 'drug-substance-1- manufacturer-1.pdf'
and the second 'drug-substance-1-manufacturer-2.pdf'.
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for the
Quality Overall Summary
Nonclinical Overview
m2-4-nonclinical-overview
m2/24-nonclin-over
Page 4-6
2.4
Nonclinical Overview
m2-4-nonclinical-overview
m2/24-nonclin-over/nonclinical-overview.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
Comment
within the document to these sub-headings.
Number
2.5
Title
Clinical Overview
19 Element
m2-5-clinical-overview
Directory m2/25-clin-over
Comment
Number
2.5
Title
Clinical Overview
Element
m2-5-clinical-overview
20
File
m2/25-clin-over/clinical-overview.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
Comment
within the document to these sub-headings.
Number
2.6
Title
Nonclinical Written and Tabulated Summaries
21 Element
m2-6-nonclinical-written-and-tabulated-summaries
Directory m2/26-nonclin-sum
Comment
Number
2.6.1
Title
Introduction
22 Element
m2-6-1-introduction
File
m2/26-nonclin-sum/introduction.pdf
Comment
23 Number
2.6.2
Title
Pharmacology Written Summary
Element
m2-6-2-pharmacology-written-summary
File
m2/26-nonclin-sum/pharmacol-written-summary.pdf
Title
Element
Directory
Comment
Number
Title
Element
18
File
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.6.3
Pharmacology Tabulated Summary
m2-6-3-pharmacology-tabulated-summary
m2/26-nonclin-sum/pharmacol-tabulated-summary.pdf
Should have further navigation via bookmarks
2.6.4
Pharmacokinetics Written Summary
m2-6-4-pharmacokinetics-written-summary
m2/26-nonclin-sum/pharmkin-written-summary.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.6.5
Pharmacokinetics Tabulated Summary
m2-6-5-pharmacokinetics-tabulated-summary
m2/26-nonclin-sum/pharmkin-tabulated-summary.pdf
Should have further navigation via bookmarks
2.6.6
Toxicology Written Summary
m2-6-6-toxicology-written-summary
m2/26-nonclin-sum/toxicology-written-summary.pdf
Typically, this logical document should consist of a single file. The CTD defines further heading levels and navigation should be provided
within the document to these sub-headings.
2.6.7
Toxicology Tabulated Summary
m2-6-7-toxicology-tabulated-summary
m2/26-nonclin-sum/toxicology-tabulated-summary.pdf
Should have further navigation via bookmarks
2.7
Clinical Summary
m2-7-clinical-summary
m2/27-clin-sum
Page 4-7
Number
Title
28 Element
File
Comment
Number
Title
29 Element
Directory
Comment
30 Number
2.7.1
Comment
Number
Title
26 Element
File
Comment
Number
Title
Element
27
File
Comment
Number
Title
24 Element
File
Comment
Number
Title
Element
25
File
Comment
Comment
Page 4-8
Number
Title
34 Element
File
Comment
35 Number
Title
Element
File
Comment
Number
Title
Element
33
File
32
Number
Title
Element
File
Comment
Number
Title
Element
31
File
Comment
Title
Element
File
2.7.6
Synopses of Individual Studies
m2-7-6-synopses-of-individual-studies
m2/27-clin-sum/synopses-indiv-studies.pdf
Page 4-9
Comment
These synopses should already be located in the Clinical Study Reports in Module 5 and should not, therefore, be repeated in Module 2. It is
considered sufficient to provide hyperlinks from the listing of the studies, located here, to the locations of the synopses in Module 5.
39
38
37
36
Page 4-10
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
3.2.S
Drug Substance - Drug Substance Name - Manufacturer
m3-2-s-drug-substance
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1
3.2.S
Drug Substance
m3-2-s-drug-substance
m3/32-body-data/32s-drug-sub
3
Quality
m3-quality
m3
Refer to the Granularity Annex of the M4 Organisation Document for guidance on the flexibility of multiple documents for Module 3
3.2
Body of Data
m3-2-body-of-data
m3/32-body-data
43
42
41
40
Page 4-11
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Comment
3.2.S.1.3
3.2.S.1.2
Structure (name, manufacturer)
m3-2-s-1-2-structure
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/structure.pdf
3.2.S.1.1
Nomenclature (name, manufacturer)
m3-2-s-1-1-nomenclature
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info/nomenclature.pdf
Typically the applicant would include the specific manufacturer(s) (and/or site) in the folder name.
3.2.S.1
General Information (name, manufacturer)
m3-2-s-1-general-information
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s1-gen-info
Where there is more than one drug substance (e.g., ranitidine hydrochloride and cimetidine) then the first drug
substance has a folder 'ranitidine-hydrochloride' and the second 'cimetidine'.
Where there is more than one manufacturer, the drug substance folder should be repeated but with an indication of
each manufacturer concerned included in the folder name, the first instance e.g., 'drug-substance-1- manufacturer-1'
and the second 'drug-substance-1-manufacturer-2'.
The folder name should always include the name of the drug substance e.g., ranitidine through inclusion of the
International Non-proprietary Name to give 'ranitidine-hydrochloride'. Similarly, for manufacturer, the folder name
should always include the name of the manufacturer e.g., ranitidine-manufacturer-1.
49
48
47
46
45
44
Page 4-12
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
3.2.S.2.5
Process Validation and/or Evaluation (name, manufacturer)
m3-2-s-2-5-process-validation-and-or-evaluation
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/process-validation.pdf
3.2.S.2.4
Controls of Critical Steps and Intermediates (name, manufacturer)
m3-2-s-2-4-controls-of-critical-steps-and-intermediates
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/control-critical-steps.pdf
3.2.S.2.3
Control of Materials (name, manufacturer)
m3-2-s-2-3-control-of-materials
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/control-of-materials.pdf
3.2.S.2.1
Manufacturer(s) (name, manufacturer)
m3-2-s-2-1-manufacturer
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manufacturer.pdf
For this document there should be only information regarding one manufacturer
3.2.S.2.2
Description of Manufacturing Process and Process Controls (name, manufacturer)
m3-2-s-2-2-description-of-manufacturing-process-and-process-controls
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manuf-process-and-controls.pdf
3.2.S.2
56
55
54
53
52
51
50
Page 4-13
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
3.2.S.4.1
Specification (name, manufacturer)
m3-2-s-4-1-specification
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s41-spec/specification.pdf
3.2.S.4.1
Specification (name, manufacturer)
m3-2-s-4-1-specification
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s41-spec
3.2.S.4
Control of Drug Substance (name, manufacturer)
m3-2-s-4-control-of-drug-substance
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub
3.2.S.3.2
Impurities (name, manufacturer)
m3-2-s-3-2-impurities
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac/impurities.pdf
3.2.S.3.1
Elucidation of Structure and Other Characteristics (name, manufacturer)
m3-2-s-3-1-elucidation-of-structure-and-other-characteristics
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac/elucidation-of-structure.pdf
3.2.S.3
Characterisation (name, manufacturer)
m3-2-s-3-characterisation
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s3-charac
3.2.S.2.6
Manufacturing Process Development (name, manufacturer)
m3-2-s-2-6-manufacturing-process-development
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s2-manuf/manuf-process-development.pdf
63
62
61
60
59
58
57
Page 4-14
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
3.2.S.4.3.2
Validation of Analytical Procedure-2
m3-2-s-4-3-validation-of-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc/validation-analyt-procedure-2.pdf
3.2.S.4.3
Validation of Analytical Procedures
m3-2-s-4-3-validation-of-analytical-procedures (name, manufacturer)
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
3.2.S.4.3.1
Validation of Analytical Procedure-1
m3-2-s-4-3-validation-of-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc/validation-analyt-procedure-1.pdf
3.2.S.4.2.3
Analytical Procedure-3
m3-2-s-4-2-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc/analytical-procedure-3.pdf
3.2.S.4.2.2
Analytical Procedure-2
m3-2-s-4-2-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc/analytical-procedure-2.pdf
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
3.2.S.4.2.1
Analytical Procedure-1
m3-2-s-4-2-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc/analytical-procedure-1.pdf
3.2.S.4.2
Analytical Procedures (name, manufacturer)
m3-2-s-4-2-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s42-analyt-proc
70
69
68
67
66
65
64
Page 4-15
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
3.2.S.5
Reference Standards or Materials (name, manufacturer)
m3-2-s-5-reference-standards-or-materials
3.2.S.5
Reference Standards or Materials (name, manufacturer)
m3-2-s-5-reference-standards-or-materials
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand
3.2.S.4.5
Justification of Specification (name, manufacturer)
m3-2-s-4-5-justification-of-specification
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s45-justif-spec/justification-of-specification.pdf
3.2.S.4.5
Justification of Specification (name, manufacturer)
m3-2-s-4-5-justification-of-specification
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s45-justif-spec
3.2.S.4.4
Batch Analyses (name, manufacturer)
m3-2-s-4-4-batch-analyses
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s44-batch-analys/batch-analyses.pdf
3.2.S.4.4
Batch Analyses (name, manufacturer)
m3-2-s-4-4-batch-analyses
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s44-batch-analys
3.2.S.4.3.3
Validation of Analytical Procedure-3
m3-2-s-4-3-validation-of-analytical-procedures
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s4-contr-drug-sub/32s43-val-analyt-proc/validation-analyt-procedure-3.pdf
77
76
75
74
73
72
71
Page 4-16
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
3.2.P
Drug Product (name, dosage form)
m3-2-p-drug-product
3.2.S.7.3
Stability Data (name, manufacturer)
m3-2-s-7-3-stability-data
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/stability-data.pdf
3.2.S.7.2
Post-approval Stability Protocol and Stability Commitment (name, manufacturer)
m3-2-s-7-2-post-approval-stability-protocol-and-stability-commitment
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/postapproval-stability.pdf
3.2.S.7.1
Stability Summary and Conclusions (name, manufacturer)
m3-2-s-7-1-stability-summary-and-conclusions
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab/stability-summary.pdf
3.2.S.7
Stability (name, manufacturer)
m3-2-s-7-stability
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s7-stab
3.2.S.6
Container Closure System (name, manufacturer)
m3-2-s-6-container-closure-system
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys/container-closure-system.pdf
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s5-ref-stand/reference-standards.pdf
Where a multiple file approach is taken for this section, the file names should indicate which reference standard is covered in the document.
3.2.S.6
Container Closure System (name, manufacturer)
m3-2-s-6-container-closure-system
m3/32-body-data/32s-drug-sub/substance-1-manufacturer-1/32s6-cont-closure-sys
82
81
80
79
78
Page 4-17
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Comment
Number
Title
Element
Directory
Directory
Development section.
Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical
3.2.P.2
Pharmaceutical Development (name, dosage form)
m3-2-p-2-pharmaceutical-development
m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev
Refer to the M4 Organisation Document: Granularity Annex for guidance on the flexibility of multiple documents for the Pharmaceutical
Development section.
3.2.P.2
Pharmaceutical Development (name, dosage form)
m3-2-p-2-pharmaceutical-development
m3/32-body-data/32p-drug-prod/product-1/32p2-pharm-dev/pharmaceutical-development.pdf
3.2.P.1
Description and Composition of the Drug Product (name, dosage form)
m3-2-p-1-description-and-composition-of-the-drug-product
m3/32-body-data/32p-drug-prod/product-1/32p1-desc-comp/description-and-composition.pdf
m3-2-p-drug-product
m3/32-body-data/32p-drug-prod/product-1
The folder name should always include the name of the drug product through inclusion of the name of the form/strength to give e.g., 'tablet5mg'. Where there is more than one drug product (e.g., powder for reconstitution and diluent) then the first drug product has a folder
'powder-for-reconstitution' and the second 'diluent'.
Refer to regional guidance for definition of what constitutes a drug product and the acceptability of more than one drug product in an
application.
3.2.P.1
Description and Composition of the Drug Product (name, dosage form)
m3-2-p-1-description-and-composition-of-the-drug-product
m3/32-body-data/32p-drug-prod/product-1/32p1-desc-comp
3.2.P
Drug Product (name, dosage form) Name
m3/32-body-data/32p-drug-prod
89
88
87
86
85
84
83
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3.2.P.3.5
Process Validation and/or Evaluation (name, dosage form)
m3-2-p-3-5-process-validation-and-or-evaluation
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/process-validation.pdf
The applicant has the option to submit one or multiple files, one for each validation or evaluation.
3.2.P.4
Control of Excipients (name, dosage form)
m3-2-p-4-control-of-excipients
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip
3.2.P.3.4
Controls of Critical Steps and Intermediates (name, dosage form)
m3-2-p-3-4-controls-of-critical-steps-and-intermediates
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/control-critical-steps.pdf
3.2.P.3.3
Description of Manufacturing Process and Process Controls (name, dosage form)
m3-2-p-3-3-description-of-manufacturing-process-and-process-controls
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manuf-process-and-controls.pdf
3.2.P.3.2
Batch Formula (name, dosage form)
m3-2-p-3-2-batch-formula
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/batch-formula.pdf
3.2.P.3.1
Manufacturer(s) (name, dosage form)
m3-2-p-3-1-manufacturers
m3/32-body-data/32p-drug-prod/product-1/32p3-manuf/manufacturers.pdf
3.2.P.3
96
95
94
93
92
91
90
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3.2.P.4.6
3.2.P.4
Control of Excipients (name, dosage form) Excipient
m3-2-p-4-control-of-excipients
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1
For a drug product containing more than one excipient, the information requested for sections 3.2.P.4.1 3.2.P.4.4 should be provided in its
entirety for each excipient. For compendial excipient(s) without additional specification tests, it is appropriate to have all information in
one file, making sure to introduce a folder for each of new documents to avoid mixing files and folders at the same level. Non-compendial
excipients should follow the structure outlined below.
3.2.P.4.1
Specifications (name, dosage form)
m3-2-p-4-1-specifications
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/specifications.pdf
See comment under 3.2.P.4.
3.2.P.4.2
Analytical Procedures (name, dosage form)
m3-2-p-4-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/analytical-procedures.pdf
See comment under 3.2.P.4.
3.2.P.4.3
Validation of Analytical Procedures (name, dosage form)
m3-2-p-4-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/validation-analyt-procedures.pdf
See comment under 3.2.P.4.
3.2.P.4.4
Justification of Specifications (name, dosage form)
m3-2-p-4-4-justification-of-specifications
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipient-1/justification-of-specifications.pdf
See comment under 3.2.P.4.
3.2.P.4.5
Excipients of Human or Animal Origin (name, dosage form)
m3-2-p-4-5-excipients-of-human-or-animal-origin
m3/32-body-data/32p-drug-prod/product-1/32p4-contr-excip/excipients-human-animal.pdf
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3.2.P.5.2.2
Analytical Procedure 2
m3-2-p-5-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-2.pdf
3.2.P.5.2
Analytical Procedures (name, dosage form)
m3-2-p-5-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
3.2.P.5.2.1
Analytical Procedure 1
m3-2-p-5-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-1.pdf
3.2.P.5.1
Specification(s) (name, dosage form)
m3-2-p-5-1-specifications
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec/specifications.pdf
3.2.P.5.1
Specification(s) (name, dosage form)
m3-2-p-5-1-specifications
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p51-spec
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod
3.2.P.5
Control of Drug Product (name, dosage form)
m3-2-p-5-control-of-drug-product
109
108
107
106
105
104
103
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3.2.P.5.4
Batch Analyses (name, dosage form)
m3-2-p-5-4-batch-analyses
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p54-batch-analys/batch-analyses.pdf
3.2.P.5.4
Batch Analyses (name, dosage form)
m3-2-p-5-4-batch-analyses
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p54-batch-analys
3.2.P.5.3.3
Validation of Analytical Procedures 3
m3-2-p-5-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc/validation-analytical-procedures-3.pdf
3.2.P.5.3.2
Validation of Analytical Procedures 2
m3-2-p-5-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc/validation-analytical-procedures-2.pdf
3.2.P.5.3.1
Validation of Analytical Procedures 1
m3-2-p-5-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc/validation-analytical-procedures-1.pdf
3.2.P.5.3
Validation of Analytical Procedures (name, dosage form)
m3-2-p-5-3-validation-of-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p53-val-analyt-proc
The example below shows how a multiple file approach, where a separate file is provided for each analytical procedure, may be organized.
3.2.P.5.2.3
Analytical Procedure 3
m3-2-p-5-2-analytical-procedures
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p52-analyt-proc/analytical-procedure-3.pdf
116
115
114
113
112
111
110
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3.2.P.6
Reference Standards or Materials (name, dosage form)
m3-2-p-6-reference-standards-or-materials
m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand/reference-standards.pdf
When a multiple file approach is taken for this section, the file names should indicate which reference standard is covered in the document.
3.2.P.7
Container Closure System (name, dosage form)
m3-2-p-7-container-closure-system
m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys
3.2.P.6
Reference Standards or Materials (name, dosage form)
m3-2-p-6-reference-standards-or-materials
m3/32-body-data/32p-drug-prod/product-1/32p6-ref-stand
3.2.P.5.6
Justification of Specifications (name, dosage form)
m3-2-p-5-6-justification-of-specifications
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec/justification-of-specifications.pdf
3.2.P.5.6
Justification of Specifications (name, dosage form)
m3-2-p-5-6-justification-of-specifications
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p56-justif-spec
3.2.P.5.5
Characterisation of Impurities (name, dosage form)
m3-2-p-5-5-characterisation-of-impurities
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p55-charac-imp/characterisation-impurities.pdf
3.2.P.5.5
Characterisation of Impurities (name, dosage form)
m3-2-p-5-5-characterisation-of-impurities
m3/32-body-data/32p-drug-prod/product-1/32p5-contr-drug-prod/32p55-charac-imp
123
122
121
120
119
118
117
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3.2.A.1
Facilities and Equipment (name, manufacturer)
m3-2-a-1-facilities-and-equipment
m3/32-body-data/32a-app/32a1-fac-equip
3.2.A
Appendices
m3-2-a-appendices
m3/32-body-data/32a-app
3.2.P.8.3
Stability Data (name, dosage form)
m3-2-p-8-3-stability-data
m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-data.pdf
3.2.P.8.2
Post-approval Stability Protocol and Stability Commitment (name, dosage form)
m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment
m3/32-body-data/32p-drug-prod/product-1/32p8-stab/postapproval-stability.pdf
3.2.P.8.1
Stability Summary and Conclusion (name, dosage form)
m3-2-p-8-1-stability-summary-and-conclusion
m3/32-body-data/32p-drug-prod/product-1/32p8-stab/stability-summary.pdf
3.2.P.8
Stability (name, dosage form)
m3-2-p-8-stability
m3/32-body-data/32p-drug-prod/product-1/32p8-stab
3.2.P.7
Container Closure System (name, dosage form)
m3-2-p-7-container-closure-system
m3/32-body-data/32p-drug-prod/product-1/32p7-cont-closure-sys/container-closure-system.pdf
Comment
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Title
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130 Number
127
126
125
124
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Comment
3.2.A.2.3
3.2.A.2.2
Adventitious Agents Safety Evaluation Report 2
m3-2-a-2-adventitious-agents-safety-evaluation
m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-2.pdf
3.2.A.2
Adventitious Agents Safety Evaluation (name, dosage form, manufacturer)
m3-2-a-2-adventitious-agents-safety-evaluation
m3/32-body-data/32a-app/32a2-advent-agent
Nonviral adventitious agents reports should be placed in this folder. For viral adventitious agents the following sub-folder structure should
be used. However, where the is more than one drug substance, drug product, manufacturer etc., a directory should be created each option
and its identity included in the directory name.
3.2.A.2.1
Adventitious Agents Safety Evaluation Report 1
m3-2-a-2-adventitious-agents-safety-evaluation
m3/32-body-data/32a-app/32a2-advent-agent/adventitious-agents-report-1.pdf
3.2.A.1.3
Facilities and Equipment Report 3
m3-2-a-1-facilities-and-equipment
m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-3.pdf
3.2.A.1.2
Facilities and Equipment Report 2
m3-2-a-1-facilities-and-equipment
m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-2.pdf
Several reports are likely to be included in this appendix. The organisation is left to the applicant to define. However, where there is more
than one manufacturer a folder should be created for each manufacturer and the identity of the manufacturer included in the directory name.
3.2.A.1.1
Facilities and Equipment Report 1
m3-2-a-1-facilities-and-equipment
m3/32-body-data/32a-app/32a1-fac-equip/facilities-and-equipment-report-1.pdf
136
135
134
133
132
131
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3.3.3
Reference 3
3.3.2
Reference 2
m3-3-literature-references
m3/33-lit-ref/reference-2.pdf
The directory/file structure would typically follow that of the drug substance section in Module 3. Refer to Regional guidances for the need
for such information to be included in the submission directly as opposed to its inclusion in a Drug Master File.
3.2.R
Regional Information
m3-2-r-regional-information
m3/32-body-data/32r-reg-info
Refer to the M4 Organisation Document: Granularity Annex for the approach to take with this section.
3.3
Literature References
m3-3-literature-references
m3/33-lit-ref
Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference).
3.3.1
Reference 1
m3-3-literature-references
m3/33-lit-ref/reference-1.pdf
3.2.A.3
Excipients Name
m3-2-a-3-excipients
m3/32-body-data/32a-app/32a3-excip-name-1
The name of any novel excipient should be included in the folder name. If there is more than one novel excipient then each folder should
have unique identification through the use of different names e.g., '32a3-excip-name-1' and '32a3-excip-name-2'.
Page 4-26
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File
Comment
m3-3-literature-references
m3/33-lit-ref/reference-3.pdf
4.2.1.1
Primary Pharmacodynamics
m4-2-1-1-primary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4211-prim-pd
4.2.1
Pharmacology
m4-2-1-pharmacology
m4/42-stud-rep/421-pharmacol
4.2
Study Reports
m4-2-study-reports
m4/42-stud-rep
4
Nonclinical Study Reports
m4-nonclinical-study-reports
m4
Page 4-27
4.2.1.1.1
Study Report 1
m4-2-1-1-primary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-1.pdf
Typically a single file should be provided for each study report in Module 4. However, where the study report is large (e.g., a
carcinogenicity study) the applicant can choose to submit the report as more than one file. In this case the text portion of the report should
be one file and the appendices may be one or more files. In choosing the level of granularity for these reports, the applicant should consider
141
that, when relevant information is changed at any point in the product's lifecycle, replacements of complete documents/files should be
provided.
Comment
Where the approach of multiple files is used it is recommended that a directory is created at the study report level and the relevant files
included within the directory.
It is possible to have the additional graphical file(s) inserted directly into the PDF file, thus making management of the file easier.
Alternatively, the applicant can choose to manage graphical files independently.
This comment is applicable to all study reports in Module 4.
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139
138
137
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146
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144
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142
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4.2.1.3
Safety Pharmacology
m4-2-1-3-safety-pharmacology
m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol
4.2.1.2.3
Study Report 3
m4-2-1-2-secondary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-3.pdf
4.2.1.2.2
Study Report 2
m4-2-1-2-secondary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-2.pdf
4.2.1.2.1
Study Report 1
m4-2-1-2-secondary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4212-sec-pd/study-report-1.pdf
4.2.1.2
Secondary Pharmacodynamics
m4-2-1-2-secondary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4212-sec-pd
4.2.1.1.3
Study Report 3
m4-2-1-1-primary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-3.pdf
4.2.1.1.2
Study Report 2
m4-2-1-1-primary-pharmacodynamics
m4/42-stud-rep/421-pharmacol/4211-prim-pd/study-report-2.pdf
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153
152
151
150
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4.2.1.4.3
Study Report 3
m4-2-1-4-pharmacodynamic-drug-interactions
m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-3.pdf
4.2.1.4.2
Study Report 2
m4-2-1-4-pharmacodynamic-drug-interactions
m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-2.pdf
4.2.1.4.1
Study Report 1
m4-2-1-4-pharmacodynamic-drug-interactions
m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact/study-report-1.pdf
m4-2-1-4-pharmacodynamic-drug-interactions
m4/42-stud-rep/421-pharmacol/4214-pd-drug-interact
4.2.1.4
Pharmacodynamic Drug Interactions
4.2.1.3.3
Study Report 3
m4-2-1-3-safety-pharmacology
m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-3.pdf
4.2.1.3.2
Study Report 2
m4-2-1-3-safety-pharmacology
m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-2.pdf
4.2.1.3.1
Study Report 1
m4-2-1-3-safety-pharmacology
m4/42-stud-rep/421-pharmacol/4213-safety-pharmacol/study-report-1.pdf
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161
160
159
158
157
156
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4.2.2.2.1
Study Report 1
m4-2-2-2-absorption
m4/42-stud-rep/422-pk/4222-absorp/study-report-1.pdf
4.2.2.2
Absorption
m4-2-2-2-absorption
m4/42-stud-rep/422-pk/4222-absorp
4.2.2.1.3
Study Report 3
m4-2-2-1-analytical-methods-and-validation-reports
m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-3.pdf
4.2.2.1.2
Study Report 2
m4-2-2-1-analytical-methods-and-validation-reports
m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-2.pdf
4.2.2.1.1
Study Report 1
m4-2-2-1-analytical-methods-and-validation-reports
m4/42-stud-rep/422-pk/4221-analyt-met-val/study-report-1.pdf
4.2.2.1
Analytical Methods and Validation Reports (if separate reports are available)
m4-2-2-1-analytical-methods-and-validation-reports
m4/42-stud-rep/422-pk/4221-analyt-met-val
4.2.2
Pharmacokinetics
m4-2-2-pharmacokinetics
m4/42-stud-rep/422-pk
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168
167
166
165
164
163
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4.2.2.4
Metabolism
m4-2-2-4-metabolism
m4/42-stud-rep/422-pk/4224-metab
4.2.2.3.3
Study Report 3
m4-2-2-3-distribution
m4/42-stud-rep/422-pk/4223-distrib/study-report-3.pdf
4.2.2.3.2
Study Report 2
m4-2-2-3-distribution
m4/42-stud-rep/422-pk/4223-distrib/study-report-2.pdf
4.2.2.3.1
Study Report 1
m4-2-2-3-distribution
m4/42-stud-rep/422-pk/4223-distrib/study-report-1.pdf
4.2.2.3
Distribution
m4-2-2-3-distribution
m4/42-stud-rep/422-pk/4223-distrib
4.2.2.2.3
Study Report 3
m4-2-2-2-absorption
m4/42-stud-rep/422-pk/4222-absorp/study-report-3.pdf
4.2.2.2.2
Study Report 2
m4-2-2-2-absorption
m4/42-stud-rep/422-pk/4222-absorp/study-report-2.pdf
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Study Report 3
m4-2-2-5-excretion
4.2.2.5.2
Study Report 2
m4-2-2-5-excretion
m4/42-stud-rep/422-pk/4225-excr/study-report-2.pdf
4.2.2.5.1
Study Report 1
m4-2-2-5-excretion
m4/42-stud-rep/422-pk/4225-excr/study-report-1.pdf
4.2.2.5
Excretion
m4-2-2-5-excretion
m4/42-stud-rep/422-pk/4225-excr
4.2.2.4.3
Study Report 3
m4-2-2-4-metabolism
m4/42-stud-rep/422-pk/4224-metab/study-report-3.pdf
4.2.2.4.2
Study Report 2
m4-2-2-4-metabolism
m4/42-stud-rep/422-pk/4224-metab/study-report-2.pdf
4.2.2.4.1
Study Report 1
m4-2-2-4-metabolism
m4/42-stud-rep/422-pk/4224-metab/study-report-1.pdf
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4.2.2.7.2
Study Report 2
m4-2-2-7-other-pharmacokinetic-studies
4.2.2.7.1
Study Report 1
m4-2-2-7-other-pharmacokinetic-studies
m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-1.pdf
4.2.2.7
Other Pharmacokinetic Studies
m4-2-2-7-other-pharmacokinetic-studies
m4/42-stud-rep/422-pk/4227-other-pk-stud
4.2.2.6.3
Study Report 3
m4-2-2-6-pharmacokinetic-drug-interactions
m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-3.pdf
4.2.2.6.2
Study Report 2
m4-2-2-6-pharmacokinetic-drug-interactions
m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-2.pdf
4.2.2.6.1
Study Report 1
m4-2-2-6-pharmacokinetic-drug-interactions
m4/42-stud-rep/422-pk/4226-pk-drug-interact/study-report-1.pdf
4.2.2.6
Pharmacokinetic Drug Interactions (nonclinical)
m4-2-2-6-pharmacokinetic-drug-interactions
m4/42-stud-rep/422-pk/4226-pk-drug-interact
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4.2.3.2
Repeat-Dose Toxicity (in order by species, by route, by duration, including supportive toxicokinetics evaluations)
4.2.3.1.3
Study Report 3
m4-2-3-1-single-dose-toxicity
m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-3.pdf
4.2.3.1.2
Study Report 2
m4-2-3-1-single-dose-toxicity
m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-2.pdf
4.2.3.1.1
Study Report 1
m4-2-3-1-single-dose-toxicity
m4/42-stud-rep/423-tox/4231-single-dose-tox/study-report-1.pdf
4.2.3.1
Single-Dose Toxicity (in order by species, by route)
m4-2-3-1-single-dose-toxicity
m4/42-stud-rep/423-tox/4231-single-dose-tox
4.2.3
Toxicology
m4-2-3-toxicology
m4/42-stud-rep/423-tox
4.2.2.7.3
Study Report 3
m4-2-2-7-other-pharmacokinetic-studies
m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-3.pdf
m4/42-stud-rep/422-pk/4227-other-pk-stud/study-report-2.pdf
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4.2.3.3.1.2
Study Report 2
4.2.3.3.1.1
Study Report 1
m4-2-3-3-1-in-vitro
m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-1.pdf
4.2.3.3.1
In vitro
m4-2-3-3-1-in-vitro
m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro
4.2.3.3
Genotoxicity
m4-2-3-3-genotoxicity
m4/42-stud-rep/423-tox/4233-genotox
4.2.3.2.3
Study Report 3
m4-2-3-2-repeat-dose-toxicity
m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-3.pdf
4.2.3.2.2
Study Report 2
m4-2-3-2-repeat-dose-toxicity
m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-2.pdf
4.2.3.2.1
Study Report 1
m4-2-3-2-repeat-dose-toxicity
m4/42-stud-rep/423-tox/4232-repeat-dose-tox/study-report-1.pdf
m4-2-3-2-repeat-dose-toxicity
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4.2.3.4.1
4.2.3.4
Carcinogenicity (including supportive toxicokinetics evaluations)
m4-2-3-4-carcinogenicity
m4/42-stud-rep/423-tox/4234-carcigen
4.2.3.3.2.3
Study Report 3
m4-2-3-3-2-in-vivo
m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-3.pdf
4.2.3.3.2.2
Study Report 2
m4-2-3-3-2-in-vivo
m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-2.pdf
4.2.3.3.2.1
Study Report 1
m4-2-3-3-2-in-vivo
m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo/study-report-1.pdf
4.2.3.3.2
In vivo (including supportive toxicokinetics evaluations)
m4-2-3-3-2-in-vivo
m4/42-stud-rep/423-tox/4233-genotox/42332-in-vivo
4.2.3.3.1.3
Study Report 3
m4-2-3-3-1-in-vitro
m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-3.pdf
m4-2-3-3-1-in-vitro
m4/42-stud-rep/423-tox/4233-genotox/42331-in-vitro/study-report-2.pdf
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4.2.3.4.2.2
Study Report 2
m4-2-3-4-2-short-or-medium-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-2.pdf
4.2.3.4.2.1
Study Report 1
m4-2-3-4-2-short-or-medium-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-1.pdf
4.2.3.4.2
Short- or medium-term studies (including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
pharmacokinetics)
m4-2-3-4-2-short-or-medium-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud
4.2.3.4.1.3
Study Report 3
m4-2-3-4-1-long-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-3.pdf
4.2.3.4.1.2
Study Report 2
m4-2-3-4-1-long-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-2.pdf
4.2.3.4.1.1
Study Report 1
m4-2-3-4-1-long-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud/study-report-1.pdf
Long-term studies (in order by species, including range-finding studies that cannot be appropriately included under repeat-dose toxicity or
pharmacokinetics)
m4-2-3-4-1-long-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42341-lt-stud
Title
4.2.3.5
Reproductive and Developmental Toxicity (including range-finding studies and supportive toxicokinetics evaluations) (If modified study
designs are used, the following subheadings should be modified accordingly)
m4-2-3-5-reproductive-and-developmental-toxicity
m4/42-stud-rep/423-tox/4235-repro-dev-tox
4.2.3.4.3.3
Study Report 3
m4-2-3-4-3-other-studies
m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-3.pdf
4.2.3.4.3.2
Study Report 2
m4-2-3-4-3-other-studies
m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-2.pdf
4.2.3.4.3.1
Study Report 1
m4-2-3-4-3-other-studies
m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud/study-report-1.pdf
4.2.3.4.3
Other studies
m4-2-3-4-3-other-studies
m4/42-stud-rep/423-tox/4234-carcigen/42343-other-stud
4.2.3.4.2.3
Study Report 3
m4-2-3-4-2-short-or-medium-term-studies
m4/42-stud-rep/423-tox/4234-carcigen/42342-smt-stud/study-report-3.pdf
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Study Report 3
4.2.3.5.2.2
Study Report 2
m4-2-3-5-2-embryo-fetal-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-2.pdf
4.2.3.5.2.1
Study Report 1
m4-2-3-5-2-embryo-fetal-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-1.pdf
4.2.3.5.2
Embryo-fetal development
m4-2-3-5-2-embryo-fetal-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev
4.2.3.5.1.3
Study Report 3
m4-2-3-5-1-fertility-and-early-embryonic-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev/study-report-3.pdf
4.2.3.5.1.2
Study Report 2
m4-2-3-5-1-fertility-and-early-embryonic-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev/study-report-2.pdf
4.2.3.5.1.1
Study Report 1
m4-2-3-5-1-fertility-and-early-embryonic-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42351-fert-embryo-dev/study-report-1.pdf
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4.2.3.5.4.2
Study Report 2
4.2.3.5.4.1
Study Report 1
m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-1.pdf
4.2.3.5.4
Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv
4.2.3.5.3.3
Study Report 3
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-3.pdf
4.2.3.5.3.2
Study Report 2
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-2.pdf
4.2.3.5.3.1
Study Report 1
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev/study-report-1.pdf
4.2.3.5.3
Prenatal and postnatal development, including maternal function
m4-2-3-5-3-prenatal-and-postnatal-development-including-maternal-function
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42353-pre-postnatal-dev
m4-2-3-5-2-embryo-fetal-development
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42352-embryo-fetal-dev/study-report-3.pdf
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4.2.3.7.1
Antigenicity
4.2.3.7
Other Toxicity Studies (if available)
m4-2-3-7-other-toxicity-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud
4.2.3.6.3
Study Report 3
m4-2-3-6-local-tolerance
m4/42-stud-rep/423-tox/4236-loc-tol/study-report-3.pdf
4.2.3.6.2
Study Report 2
m4-2-3-6-local-tolerance
m4/42-stud-rep/423-tox/4236-loc-tol/study-report-2.pdf
4.2.3.6.1
Study Report 1
m4-2-3-6-local-tolerance
m4/42-stud-rep/423-tox/4236-loc-tol/study-report-1.pdf
4.2.3.6
Local Tolerance
m4-2-3-6-local-tolerance
m4/42-stud-rep/423-tox/4236-loc-tol
4.2.3.5.4.3
Study Report 3
m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
m4/42-stud-rep/423-tox/4235-repro-dev-tox/42354-juv/study-report-3.pdf
m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-and-or-further-evaluated
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4.2.3.7.2.3
4.2.3.7.2.2
Study Report 2
m4-2-3-7-2-immunotoxicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-2.pdf
4.2.3.7.2.1
Study Report 1
m4-2-3-7-2-immunotoxicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-1.pdf
4.2.3.7.2
Immunotoxicity
m4-2-3-7-2-immunotoxicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox
4.2.3.7.1.3
Study Report 3
m4-2-3-7-1-antigenicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-3.pdf
4.2.3.7.1.2
Study Report 2
m4-2-3-7-1-antigenicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-2.pdf
4.2.3.7.1.1
Study Report 1
m4-2-3-7-1-antigenicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42371-antigen/study-report-1.pdf
m4-2-3-7-1-antigenicity
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4.2.3.7.4.1
Study Report 1
m4-2-3-7-4-dependence
m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-1.pdf
4.2.3.7.4
Dependence
m4-2-3-7-4-dependence
m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep
4.2.3.7.3.3
Study Report 3
m4-2-3-7-3-mechanistic-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-3.pdf
4.2.3.7.3.2
Study Report 2
m4-2-3-7-3-mechanistic-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-2.pdf
4.2.3.7.3.1
Study Report 1
m4-2-3-7-3-mechanistic-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud/study-report-1.pdf
4.2.3.7.3
Mechanistic studies (if not included elsewhere)
m4-2-3-7-3-mechanistic-studies
m4/42-stud-rep/423-tox/4237-other-tox-stud/42373-mechan-stud
Study Report 3
m4-2-3-7-2-immunotoxicity
m4/42-stud-rep/423-tox/4237-other-tox-stud/42372-immunotox/study-report-3.pdf
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4.2.3.7.6
Impurities
m4-2-3-7-6-impurities
m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp
4.2.3.7.5.3
Study Report 3
m4-2-3-7-5-metabolites
m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-3.pdf
4.2.3.7.5.2
Study Report 2
m4-2-3-7-5-metabolites
m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-2.pdf
4.2.3.7.5.1
Study Report 1
m4-2-3-7-5-metabolites
m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab/study-report-1.pdf
4.2.3.7.5
Metabolites
m4-2-3-7-5-metabolites
m4/42-stud-rep/423-tox/4237-other-tox-stud/42375-metab
4.2.3.7.4.3
Study Report 3
m4-2-3-7-4-dependence
m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-3.pdf
Study Report 2
m4-2-3-7-4-dependence
m4/42-stud-rep/423-tox/4237-other-tox-stud/42374-dep/study-report-2.pdf
265
264
263
262
261
260
259
Page 4-45
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Comment
Number
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File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
4.2.3.7.7.3
Study Report 3
m4-2-3-7-7-other
m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-3.pdf
4.2.3.7.7.2
Study Report 2
m4-2-3-7-7-other
m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-2.pdf
m4-2-3-7-7-other
m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other/study-report-1.pdf
4.2.3.7.7.1
Study Report 1
4.2.3.7.7
Other
m4-2-3-7-7-other
m4/42-stud-rep/423-tox/4237-other-tox-stud/42377-other
4.2.3.7.6.3
Study Report 3
m4-2-3-7-6-impurities
m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-3.pdf
4.2.3.7.6.2
Study Report 2
m4-2-3-7-6-impurities
m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-2.pdf
4.2.3.7.6.1
Study Report 1
m4-2-3-7-6-impurities
m4/42-stud-rep/423-tox/4237-other-tox-stud/42376-imp/study-report-1.pdf
269
268
267
266
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4.3.3
Reference 3
m4-3-literature-references
m4/43-lit-ref/reference-3.pdf
4.3.2
Reference 2
m4-3-literature-references
m4/43-lit-ref/reference-2.pdf
4.3
Literature References
m4-3-literature-references
m4/43-lit-ref
Copies of literature references should ordinarily be submitted as individual files (i.e., one for each reference).
4.3.1
Reference 1
m4-3-literature-references
m4/43-lit-ref/reference-1.pdf
276
275
274
273
272
271
270
Page 4-47
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Comment
Number
Title
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Comment
Number
Title
Element
Directory
5.3.1.1.1
Study Report 1
m5-3-1-1-bioavailability-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-1
5.3.1.1
Bioavailability (BA) Study Reports
m5-3-1-1-bioavailability-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep
5.3.1
Reports of Biopharmaceutic Studies
m5-3-1-reports-of-biopharmaceutic-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud
5.3
Clinical Study Reports
m5-3-clinical-study-reports
m5/53-clin-stud-rep
5.2
Tabular Listing of all Clinical Studies
m5-2-tabular-listing-of-all-clinical-studies
m5/52-tab-list/tabular-listing.pdf
5.2
Tabular Listing of all Clinical Studies
m5-2-tabular-listing-of-all-clinical-studies
m5/52-tab-list
5
Clinical Study Reports
m5-clinical-study-reports
m5
Page 4-48
The applicants should ordinarily provide the study reports as multiple files (a synopsis, a main body and appropriate appendices).
Appendices should be organized in accordance with the ICH E3 guideline which describes the content and format of the clinical study
report. In choosing the level of granularity for reports the applicant should consider that, when relevant information is changed at any point
in the product's lifecycle, replacements of complete documents/files should be provided.
Comment
It is possible to have the additional graphic file(s) inserted directly into the PDF file, thus making management of the file easier.
Alternatively, the applicant can choose to manage these graphic files independently.
This comment is applicable to all study reports in Module 5.
A directory should be created for each study and the files associated with the study report should be organized within the directory.
Number
5.3.1.1.2
Title
Study Report 2
277 Element
m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-2
Comment
Number
5.3.1.1.3
Title
Study Report 3
278 Element
m5-3-1-1-bioavailability-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5311-ba-stud-rep/study-report-3
Comment
Number
5.3.1.2
Title
Comparative BA and Bioequivalence (BE) Study Reports
279 Element
m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep
Comment
Number
5.3.1.2.1
Title
Study Report 1
280 Element
m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep/study-report-1
Comment
Number
5.3.1.2.2
Title
Study Report 2
281 Element
m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
Directory m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep/study-report-2
Comment
282 Number
5.3.1.2.3
Title
Study Report 3
289
288
287
286
285
284
283
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5.3.1.4.2
Study Report 2
5.3.1.4.1
Study Report 1
m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met/study-report-1
5.3.1.4
Reports of Bioanalytical and Analytical Methods for Human Studies
m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met
5.3.1.3.3
Study Report 3
m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep/study-report-3
5.3.1.3.2
Study Report 2
m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep/study-report-2
5.3.1.3.1
Study Report 1
m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep/study-report-1
5.3.1.3
In vitro In vivo Correlation Study Reports
m5-3-1-3-in-vitro-in-vivo-correlation-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5313-in-vitro-in-vivo-corr-stud-rep
m5-3-1-2-comparative-ba-and-bioequivalence-study-reports
m5/53-clin-stud-rep/531-rep-biopharm-stud/5312-compar-ba-be-stud-rep/study-report-3
296
295
294
293
292
291
290
Page 4-50
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5.3.2.2
Reports of Hepatic Metabolism and Drug Interaction Studies
5.3.2.1.3
Study Report 3
m5-3-2-1-plasma-protein-binding-study-reports
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep/study-report-3
5.3.2.1.2
Study Report 2
m5-3-2-1-plasma-protein-binding-study-reports
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep/study-report-2
5.3.2.1.1
Study Report 1
m5-3-2-1-plasma-protein-binding-study-reports
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep/study-report-1
5.3.2.1
Plasma Protein Binding Study Reports
m5-3-2-1-plasma-protein-binding-study-reports
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5321-plasma-prot-bind-stud-rep
5.3.2
Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat
5.3.1.4.3
Study Report 3
m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met/study-report-3
m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-human-studies
m5/53-clin-stud-rep/531-rep-biopharm-stud/5314-bioanalyt-analyt-met/study-report-2
303
302
301
300
299
298
297
Page 4-51
Element
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Comment
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Number
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Comment
Number
Title
5.3.2.3.3
Study Report 3
5.3.2.3.2
Study Report 2
m5-3-2-3-reports-of-studies-using-other-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-2
5.3.2.3.1
Study Report 1
m5-3-2-3-reports-of-studies-using-other-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-1
5.3.2.3
Reports of Studies Using Other Human Biomaterials
m5-3-2-3-reports-of-studies-using-other-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat
5.3.2.2.3
Study Report 3
m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud/study-report-3
5.3.2.2.2
Study Report 2
m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud/study-report-2
5.3.2.2.1
Study Report 1
m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud/study-report-1
m5-3-2-2-reports-of-hepatic-metabolism-and-drug-interaction-studies
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5322-rep-hep-metab-interact-stud
310
309
308
307
306
305
304
Page 4-52
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Number
Title
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Comment
Number
Title
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Comment
Number
5.3.3.2.1
5.3.3.2
Patient PK and Initial Tolerability Study Reports
m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep
5.3.3.1.3
Study Report 3
m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep/study-report-3
5.3.3.1.2
Study Report 2
m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep/study-report-2
m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep/study-report-1
5.3.3.1.1
Study Report 1
5.3.3.1
Healthy Subject PK and Initial Tolerability Study Reports
m5-3-3-1-healthy-subject-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5331-healthy-subj-pk-init-tol-stud-rep
5.3.3
Reports of Human Pharmacokinetic (PK) Studies
m5-3-3-reports-of-human-pharmacokinetics-pk-studies
m5/53-clin-stud-rep/533-rep-human-pk-stud
m5-3-2-3-reports-of-studies-using-other-human-biomaterials
m5/53-clin-stud-rep/532-rep-stud-pk-human-biomat/5323-stud-other-human-biomat/study-report-3
317
316
315
314
313
312
311
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Comment
Number
Title
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Comment
Number
5.3.3.4
5.3.3.3.3
Study Report 3
m5-3-3-3-intrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-3
5.3.3.3.2
Study Report 2
m5-3-3-3-intrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-2
5.3.3.3.1
Study Report 1
m5-3-3-3-intrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep/study-report-1
5.3.3.3
Intrinsic Factor PK Study Reports
m5-3-3-3-intrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5333-intrin-factor-pk-stud-rep
5.3.3.2.3
Study Report 3
m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep/study-report-3
5.3.3.2.2
Study Report 2
m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep/study-report-2
Study Report 1
m5-3-3-2-patient-pk-and-initial-tolerability-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5332-patient-pk-init-tol-stud-rep/study-report-1
323
322
321
320
319
318
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Comment
Number
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Comment
Number
Title
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Comment
Number
Title
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Comment
5.3.3.5.2
Study Report 2
m5-3-3-5-population-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep/study-report-2
5.3.3.5.1
Study Report 1
m5-3-3-5-population-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep/study-report-1
5.3.3.5
Population PK Study Reports
m5-3-3-5-population-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep
5.3.3.4.3
Study Report 3
m5-3-3-4-extrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep/study-report-3
5.3.3.4.2
Study Report 2
m5-3-3-4-extrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep/study-report-2
5.3.3.4.1
Study Report 1
m5-3-3-4-extrinsic-factor-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5334-extrin-factor-pk-stud-rep/study-report-1
330
329
328
327
326
325
324
Page 4-55
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Number
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Title
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Comment
Number
Title
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Directory
5.3.4.2
Patient PD and PK/PD Study Reports
m5-3-4-2-patient-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep
5.3.4.1.3
Study Report 3
m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep/study-report-3
5.3.4.1.2
Study Report 2
m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep/study-report-2
5.3.4.1.1
Study Report 1
m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep/study-report-1
5.3.4.1
Healthy Subject PD and PK/PD Study Reports
m5-3-4-1-healthy-subject-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5341-healthy-subj-pd-stud-rep
5.3.4
Reports of Human Pharmacodynamic (PD) Studies
m5-3-4-reports-of-human-pharmacodynamics-pd-studies
m5/53-clin-stud-rep/534-rep-human-pd-stud
5.3.3.5.3
Study Report 3
m5-3-3-5-population-pk-study-reports
m5/53-clin-stud-rep/533-rep-human-pk-stud/5335-popul-pk-stud-rep/study-report-3
5.3.5
Reports of Efficacy and Safety Studies
m5-3-5-reports-of-efficacy-and-safety-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud
5.3.4.2.3
Study Report 3
m5-3-4-2-patient-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep/study-report-3
5.3.4.2.2
Study Report 2
m5-3-4-2-patient-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep/study-report-2
5.3.4.2.1
Study Report 1
m5-3-4-2-patient-pd-and-pk-pd-study-reports
m5/53-clin-stud-rep/534-rep-human-pd-stud/5342-patient-pd-stud-rep/study-report-1
Page 4-56
5.3.5
Reports of Efficacy and Safety Studies - Indication Name
m5-3-5-reports-of-efficacy-and-safety-studies
335
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1
The folder name should always include the indication being claimed, for example, 'asthma' (abbreviated if appropriate). Where there is
Comment
more than one indication (e.g., asthma and migraine), then the first indication has a folder 'asthma' and the second 'migraine'.
Number
5.3.5.1
Title
Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
336 Element
m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
Directory m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr
Comment
337 Number
5.3.5.1.1
Title
Study Report 1
Element
m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
334
333
332
331
Comment
Number
Title
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Comment
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344
343
342
341
340
339
338
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Comment
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Comment
Number
Title
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Comment
Number
Title
Element
5.3.5.3
Reports of Analyses of Data from More than One Study
m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
5.3.5.2.3
Study Report 3
m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr/study-report-3
5.3.5.2.2
Study Report 2
m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr/study-report-2
5.3.5.2.1
Study Report 1
m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr/study-report-1
5.3.5.2
Study Reports of Uncontrolled Clinical Studies
m5-3-5-2-study-reports-of-uncontrolled-clinical-studies
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5352-stud-rep-uncontr
5.3.5.1.3
Study Report 3
m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-3
5.3.5.1.2
Study Report 2
m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-2
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5351-stud-rep-contr/study-report-1
351
350
349
348
347
346
345
Page 4-58
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
5.3.5.4.3
Study Report 3
m5-3-5-4-other-study-reports
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep/study-report-2
5.3.5.4.2
Study Report 2
5.3.5.4.1
Study Report 1
m5-3-5-4-other-study-reports
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep/study-report-1
5.3.5.4
Other Study Reports
m5-3-5-4-other-study-reports
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep
5.3.5.3.3
Study Report 3
m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud/study-report-3
5.3.5.3.2
Study Report 2
m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud/study-report-2
5.3.5.3.1
Study Report 1
m5-3-5-3-reports-of-analyses-of-data-from-more-than-one-study
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud/study-report-1
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5353-rep-analys-data-more-one-stud
5.3.7.1
Study 1
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-1
5.3.7
Case Report Forms and Individual Patient Listings
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl
5.3.6
Reports of Postmarketing Experience
m5-3-6-reports-of-postmarketing-experience
m5/53-clin-stud-rep/536-postmark-exp
m5-3-5-4-other-study-reports
m5/53-clin-stud-rep/535-rep-effic-safety-stud/indication-1/5354-other-stud-rep/study-report-3
Page 4-59
5.3.7.1.1
Document/Dataset 1
m5-3-7-case-report-forms-and-individual-patient-listings
355
m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-1.pdf
The filename and extension should include the description of the file and appropriate file extension according to Appendix 2. Reference
Comment
should be made to regional guidance for the acceptability of submission of datasets
Number
5.3.7.1.2
Title
Document/Dataset 2
356 Element
m5-3-7-case-report-forms-and-individual-patient-listings
File
m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-2.pdft
Comment
Number
5.3.7.1.3
Title
Document/Dataset 3
357 Element
m5-3-7-case-report-forms-and-individual-patient-listings
File
m5/53-clin-stud-rep/537-crf-ipl/study-1/filename-3.pdf
Comment
354
353
352
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
364
363
362
361
360
359
358
Page 4-60
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
5.3.7.3.2
Document/Dataset 2
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-2.pdf
5.3.7.3
Study 3
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-3
define element
5.3.7.3.1
Document/Dataset 1
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-1.pdf
5.3.7.2.3
Document/Dataset 3
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-3.pdf
5.3.7.2.2
Document/Dataset 2
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-2.pdf
5.3.7.2
Study 2
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-2
define element
5.3.7.2.1
Document/Dataset 1
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-2/filename-1.pdf
369
368
367
366
365
Page 4-61
Comment
Number
Title
Element
File
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
Comment
5.4.3
Reference 3
m5-4-literature-references
m5/54-lit-ref/reference-3.pdf
5.4.2
Reference 2
m5-4-literature-references
m5/54-lit-ref/reference-2.pdf
5.4
Literature References
m5-4-literature-references
m5/54-lit-ref
Copies of literature references should ordinarily be submitted as individual files (i.e,. one for each reference).
5.4.1
Reference 1
m5-4-literature-references
m5/54-lit-ref/reference-1.pdf
5.3.7.3.3
Document/Dataset 3
m5-3-7-case-report-forms-and-individual-patient-listings
m5/53-clin-stud-rep/537-crf-ipl/study-3/filename-3.pdf
Page 4-62
Comment
Number
Title
374 Element
File
Comment
Number
Title
375 Element
File
Comment
376 Number
Title
Element
373
372
371
370
Number
Title
Element
Directory
Comment
Number
Title
Element
Directory
Comment
Number
Title
Element
File
Comment
Number
Title
Element
File
util/dtd/us-regional-1-0.dtd
DTD for the US specific documentation
util/dtd/jp-regional-1-0.dtd
DTD for the Japan specific documentation
util/dtd/eu-regional-1-0.dtd
util/dtd/ich-ectd-3-2.dtd
DTD for the instance the version used to create the eCTD submission must be included
util/dtd
DTDs it is not necessary to include regional DTDs other than the one for the region to which the application is being made
util
utilities
util/style/ectd-1-0.xsl
util/style
Directory for style sheets default (ICH) and applicant specific stylesheets
util/dtd/xx-regional-1-0.dtd
DTD for the xx specific documentation, where xx is a two character country code from ISO-3166-1
Page 4-63
Comment The specific version of the eCTD stylesheet used by the applicant as a reference during the creation of the submission should be included.
File
378 Element
Title
File
Comment
Number
Title
377 Element
Directory
Comment
Number
Region
European Union
Food And Drug Administration,
USA
Ministry of Health, Labour and
Welfare, Japan
Health Canada
Internet Address
http://www.emea.eu.int
http://www.fda.gov/cber
http://www.fda.gov/cder
http://www.mhlw.go.jp
http://www.nihs.go.jp
http://www.hc-sc.gc.ca/hpbdgps/therapeut
e-submission@nihs.go.jp
mike_ward@hc-sc.gc.ca
Submission Addresses
Submissions should be sent directly to the appropriate regulatory authority. Information needed to send
physical media to each regulatory authority is found at the reference location in Table 5-2.
Table 5-2
Regulatory Authority
EMEA, European Union
or national agencies
Ministry of Health, Labour and Welfare, Japan
Food and Drug Administration, United States of
America
Health Canada, Health Protection Branch, Canada
Page 5-1
Reference location
http://www.eudra.org/
http://heads.medagencies.org
http://www.mhlw.go.jp
http://www.nihs.go.jp
http://www.fda.gov/
http://www.hc-sc.gc.ca/hpb-dgps/therapeut
Media
Refer to the M2 recommendations on the ICH Website for a list of media types accepted by all ICH
regions.
Cover Letter
Applicants should provide a cover letter as a PDF file (cover.pdf). A paper cover letter should also be
included with non-electronic portions of the submission (such as forms with signatures or seals, and
certifications). The cover letter should include:
Transport
Secure data exchange over the Internet is the recommended means for transporting submissions. However,
until the regulatory authorities can develop secure electronic gateways, submissions should continue to be
physically transported by courier or registered mail.
Security
An MD5 checksum should be included for each physical file in the eCTD. The checksum allows the
recipient to verify integrity of the physical files in the submission. The XML eCTD DTD provides the
location of the files and a tag name contains the checksums.
A checksum of the XML eCTD instance should also be included. Applicants should name this checksum
file index-md5.txt and include it as a file in the same directory as the XML eCTD instance. Applicants
should print the contents of the index-md5.txt file and include the paper copy with the paper cover letter for
the submission.
An applicant can provide the eCTD as an encrypted file in accordance with the ICH M2 Recommendation
4.1, if the regulatory body has implemented it. This solution allows the eCTD to be encrypted and
transferred over the Internet (if Internet receipt is implemented regionally) or to be encrypted on one of the
approved physical media standards. The purpose of encryption is to protect the privacy of the confidential
information and to ensure it is only available to the authorized receiver. Encryption is always appropriate
when the eCTD is sent via the Internet.
Encryption is not considered necessary if the information is sent using a physical media, although
encryption is an option. The applicant should assume all liability for the media until it is delivered to the
regulatory authority.
Page 5-2
Applicants should not include any file level security settings or password protection for individual files in
the eCTD. Applicants should allow printing, changes to the document, selecting text and graphics, and
adding or changing notes and form fields. Internal security and access control processes in the regulatory
authority should maintain the integrity of the submitted files.
Receipt
Upon arrival at the regulatory authority, the submission is archived according to local regulations. A readonly copy of the submission is then made available to the review community in the regulatory authority.
This is typically done by placing the copy on a network server.
Acknowledgment
Each regulatory authority should acknowledge the receipt of the eCTD submission according to the policy
and procedure of the individual regulatory authority. Applicants should use the address in Table 5-1 to find
guidance regarding acknowledgments.
Page 5-3
Sequence number
0000
0001
ctd-123456
0002
ctd-123456
nnnn
Page 6-1
Type of submission
Original Submission
First amendment, supplement or
variation
Second amendment, supplement
or variation
Nth amendment, supplement or
variation
Figure 6-1
You should submit the XML backbone as a single file named index.xml, which should be placed in the
submission sequence number folder for that submission. In the example shown in Figure 6-1, there should
be an index.xml file in folder 0000, folder 0001 and folder 0002. The MD5 checksum file, indexmd5.txt, should be in each folder with the corresponding index.xml file. The DTD for index.xml should be
in the util folder for each submission.
The regional administrative XML backbone file, if supplied, should be in the region specific module 1
folder for each submission. The DTD for the regional XML backbone file should be in the util folder for
each submission.
Table 6-2 presents the file locations for the example in Figure 6-1.
Table 6-2
Submission Folder
ctd-123456/0000
ctd-123456/0000/m1/us
ctd-123456/0000/util
ctd-123456/0001
ctd-123456/0001/m1/us
ctd-123456/0001/util/dtd
ctd-123456/0002
ctd-123456/0002/m1/us
ctd-123456/0002/util/dtd
Files
index.xml
index-md5.txt
us-regional.xml
ich-ectd-3-2.dtd
us-regional-1-0.dtd
index.xml
index-md5.txt
us-regional.xml
ich-ectd-3-2.dtd
us-regional-1-0.dtd
index.xml
index-md5.txt
us-regional.xml
ich-ectd-3-2.dtd
us-regional-1-0.dtd
Lifecycle Management
It is important for the recipients of an eCTD to be able to establish the location of the submission in the
lifecycle of a product.
The eCTD is capable of containing initial submissions, supplements, amendments, and variations. There
are no uniform definitions for these terms in the three regions, but amendments and supplements are terms
used in the United States. Variations apply in Europe. The variations, supplements, and amendments are
used to provide additional information to an original regulatory dossier. For example, if a new
manufacturer for the drug substance were being proposed, this would result in submission of an amendment
or supplement to the FDA and a variation to Europe. When regulatory authorities request additional
information, the information is also provided as a variation, supplement, or amendment to the original
Page 6-2
submission. Therefore, the regulatory agencies should have a way to manage the lifecycle of the
submission. This function should be provided by each regulatory authority in the form of guidance that can
include regional DTDs and specifications. The relevant regional DTD should be referenced in the eCTD
DTD by the applicant.
The eCTD DTD provides some facilities for lifecycle management at the file level but does not fully
support the life cycle at the submission level. When revisions are sent to a regulatory authority, the new
file should be submitted as a leaf element associated with the same tag name as the file being amended or
deleted. The modified-file attribute of the leaf element should contain the leaf ID of the file being
amended, replaced, or deleted. This will allow the regulatory authority to accurately locate the original file
and update the original files status. A detailed description of modified-file is provided in the next section.
Operation Attribute
The operation attribute is a key to managing each individual file in a submission. The applicant uses the
operation attribute to tell the regulatory authority how the applicant intends the files in the submission to be
used. The operation attribute describes the relation between files in subsequent submissions during the life
cycle of a medicinal product. In the very first submission all the files will be new. In the second, third, and
subsequent submissions, all the newly submitted files can have different operation attributes due to having
or not having a relation with previously submitted files. Table 6-2 describes the meaning of each allowed
value of the operation attribute.
Table 6-3 Understanding the Operation Attribute
Operation
attribute
value
New
Append
Replace
Delete
Meaning
The file has no relationship with files submitted
previously.
This means there is an existing file to which this new
file should be associated. (e.g., providing missing or
new information to that file). It is recommended that
append not be used to associate two files in the same
submission (e.g., splitting a file due to size restrictions).
This means there is an existing file that this new file
replaces.
There is no new file submitted in this case. Instead, the
leaf has the operation of delete and the modifiedfile attribute identifies the file in a previous submission
that is to be considered no longer relevant to the review.
Current Appended
Current
Replaced
No longer
relevant to the
review
The purpose of the modified-file attribute is to provide the location of a document that is being modified
(i.e. replaced, appended or deleted) by the leaf element. The modified-file attribute should have a value
when the operation attribute has a value of append, replace or delete. The modified-file attribute points to
the index.xml file and the leaf ID of the file being altered.
An example of a modified file attribute value is provided below:
modified-file="../0001/index.xml#a1234567"
This would provide the information needed to locate the file with the leaf element ID assigned as
"a1234567" and provided in the sequence folder numbered "0001".
Page 6-3
If a modified-file attribute is presented with no value (i.e. no characters or spaces between the quotation
marks, modified-file="") it will be the same as not including the attribute in the leaf element.
The following case examples show the use of each of the operation attribute values. These examples do not
cover all possible situations. Consult the appropriate regulatory authority if you have specific questions
about the use of the operation attribute. When actually populating the XML instance, use the leaf ID to
refer to files.
Case 1 The first submission of a dossier.
Submission
sequence #
0000
File name
0000\\structure.pdf
Table 6-4
Operation
File Being
Modified
New
Case 2 Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is a
subsequent amendment or variation in which the applicant intends to completely replace the structure.pdf
file in submission 0000. The intent is to keep the original structure.pdf for historical purposes but to
consider only the contents of the 0001\\structure.pdf as relevant to the review. These two submissions
could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf, and this file is the current
version of this file.
- Submission 0001, which is submitted at a later time, is the submission of the file
structure.pdf, which is now current and replaces the file structure.pdf in submission 0000.
Table 6-5
Submission
File name
Operation File Being Modified Sample logical display
sequence #
in a review tool
0000
0000\\structure.pdf New
structure.pdf (current)
0001
0001\\structure.pdf Replace
0000\\structure.pdf structure.pdf (replaced)
structure.pdf (current)
Case 3 Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is an
amendment or variation where the applicant intends to add new information to the original structure.pdf
file, which was submitted in submission 0000. The intent is to have the reviewer consider the contents of
both files relevant to the submission. These two submissions could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf, and this file is the current
version of this file.
- Submission 0001, submitted at a later time, is the submission of the file structure.pdf, which
is the current file but contains information that should be appended to file structure.pdf in
submission 0000. Both files should be considered relevant to the review of the dossier.
Submission
sequence #
File name
Table 6-6
Operation Modified file
0000
0001
0000\\structure.pdf
0001\\structure.pdf
New
Append
0000\...\structure.pdf
Sample logical
display in a review
tool
structure.pdf (current)
structure.pdf (current appended)
structure.pdf (current)
Case 4 Two submissions. Submission 0000 is the first submission of a dossier. Submission 0001 is an
amendment or variation where the applicant intends to delete a file in the previous submission. The intent
Page 6-4
is to have the reviewer disregard the contents of the original file, possibly because it should not have been
submitted with the original dossier. These two submissions could be described as follows:
- Submission 0000 is the first submission of the file structure.pdf and this file is the current
version of this file.
- Submission 0001, submitted at a later time, requests that the file structure.pdf in submission
0000 be deleted and no longer considered relevant to the review of the dossier.
Submission
sequence #
0000
0001
File name
0000\...\structure.pdf
Table 6-7
Operation File Being
Modified
New
Delete
0000\...\structure.pdf
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
m1-administrative-information-and-prescribing-information
m2-common-technical-document-summaries
m3-quality
m4-nonclinical-study-reports
m5-clinical-study-reports
Each of the 5 modules is divided into sub elements, each with a distinct <tag> that represents a CTD table
of contents location. The steps should be completed as shown in the following example, where all files are
submitted for modules 1 through 5:
1.
2.
3.
4.
5.
You should select a tag element that best corresponds to the CTD table of contents location for a
document or file being submitted. For example, select the tag <m2-4-nonclinical-overview> to submit
the nonclinical overview document.
You should create a child <leaf> element underneath the <m2-4-nonclinical-overview> tag.
You should provide the relative location and file name of the actual file containing the nonclinical
overview in the xlink:href attribute for the <leaf> element.
You should provide a descriptive title for the file that contains the nonclinical overview in the <title>
element of the <leaf>.
You should provide information for the appropriate attributes of the <leaf> element as described in
Table 6-8.
The table 6-8 describes each of these elements and attributes in further detail. In the current review
environment, the following leaf attributes are the most useful to the end user:
ID
xml:lang
checksum
checksum-type
modified-file
operation
Page 6-7
application-version
xlink:href
Table 6-8
Element
Attribute
Any table of
contents tag
such as <m24nonclinicaloverview>
<leaf>
Page 6-8
Description/Instructions
Example
A table of contents tag represents a
grouping of one or more files related
to a specific section of the Common
Technical Document.
One or more child <leaf> elements
can be declared for a parent table of
contents tag.
It is possible to extend a table of
contents tag by providing a <nodeextension> element. This can be done
at the lowest level of the defined table
of contents tags but should be done
only when absolutely necessary. See
the section Instructions for extending
eCTD tag elements in this appendix.
ID
A unique identifier for this location in id403 (note: At this level, ID is optional
the XML instance.
and may provide for navigation within
the index.
xml:lang
The primary language used by the
En
files in this entire section of the
submission. Use ISO-639 standard
language abbreviations
A leaf corresponds to a file.
One or more child leaf elements can
be submitted for a parent table of
contents tag.
application- The version of the software
PDF 1.3
version
application that was used to create this
file.
font-library Commercial name of fonts/font set
used to create the document.
ID
Unique identifier for this file in the
id050520
XML instance. Leaf ID must start
with a character.
checksum
The checksum value for the file being e854d3002c02a61fe5cbe926fd97b001
submitted.
checksum- The checksum algorithm used.
MD5
type
modifiedThe purpose of the modified-file
modifiedfile
attribute is to provide the location of a file="../0001/index.xml#a1234567"
document that is being modified (i.e.
replaced, appended or deleted) by the
leaf element. The modified-file
attribute should have a value when the
operation attribute has a value of
append, replace or delete. The
modified-file attribute points to the
index.xml file and the leaf ID of the
file being altered.
Element
<title>
Attribute
operation
Description/Instructions
Indicates the operation to be
performed on the modified-file.
You should select one of the
following valid values:
new
replace
append
delete
See the section Operation Attribute in
this appendix for details on the
meaning of these values.
version
The file submitters internal version
number or version identification for
the report.
xlink:actuate Not Currently Used
xlink:href
Provide the pointer to the actual file.
Use the relative path to the file and
the file name.
xlink:role
Not Currently Used
xlink:show Not Currently Used.
xlink:type Fixed value of simple.
keywords
Not Currently Used
This element is associated with a
leaf and provides a description of
the file being submitted.
ID
Unique identifier for this location in
the XML instance. Leaf ID must start
with a character.
Example
New
V23.5
0000/m2/27-clin-sum/literaturereferences.pdf
simple
study report 1234
a1234567
This submission includes the file clinical-overview.pdf in the relative directory m2/25-clin-over/ (i.e.
the one starting below the dossier number directory). The file is new and has a descriptive name of
Clinical Overview
7
Note that these XML examples are examples only and do not necessarily contain all of the elements and
attributes that you should use when preparing an eCTD submission.
Page 6-9
The regional review application should treat this as a new submission to be associated with the submission
identified in CTD module 1, which is region specific.
If this is the first submission for Dossier CTD 123456, all the files in this submission are in the ctd123456\0000 directory and below.
Table 6-9
Element
Attribute
<m2-7-3-summary-of-clinical-efficacy>
Indication
<m5-3-5-reports-of-efficacy-and-safety-studies>
Indication
Description/Instructions
Example
pain
pain
Note that the indication attribute is used by the regulatory authority to apply to all the table of contents tags
beneath the <m2-7-3-summary-of-clinical-efficacy> and <m5-3-5-reports-of-efficacy-and-safety-studies>
tags. This is an example of a section of the instance showing the submission of information about two
indications:
<?xml version = "1.0" encoding = "UTF-8"?>
<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-2.dtd">
<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<m2-common-technical-document-summaries>
<m2-7-clinical-summary>
<m2-7-3-summary-of-clinical-efficacy indication = "pain">
<leaf ID=s123456operation = "new" xlink:type = "simple"
checksum-type=md5 checksum =
"e854d3002c02a61fe5cbe926fd973401"
Page 6-10
xlink:href =
"m2/27-clin-sum/summary-clin-efficacy-pain.pdf">
<title>pain efficacy summary</title>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>
<m2-7-3-summary-of-clinical-efficacy indication = "nausea">
<leaf ID=a123457 operation = "new" xlink:type = "simple"
checksum-type=md5 checksum =
"e854d3002c02a61fe54be926fd973401"
xlink:href =
"m2/27-clin-summ/summary-clin-efficacy-nausea.pdf">
<title>nausea efficacy summary</title>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>
</m2-7-clinical-summary>
</m2-common-technical-document-summaries>
<m5-clinical-study-reports>
<m5-3-clinical-study-reports>
<m5-3-5-reports-of-efficacy-and-safety-studies indication = "pain">
<leaf ID=a123458 operation = "new" xlink:type = "simple" checksumtype=md5
checksum =
"e854d3002c02a61fe544e926fd973401"
xlink:href =
"m5/53-clin-stud-rep/535-rep-eff-safety-stud/pain/pain-sr1.pdf">
<title>pain study report 1</title>
</leaf>
</m5-3-5-reports-of-efficacy-and-safety-studies>
<m5-3-5-reports-of-efficacy-and-safety-studies indication = "nausea">
<leaf ID=a123459 operation = "new" xlink:type = "simple" checksumtype=md5 checksum =
"e854d3002c02a614e54be926fd973401"
xlink:href =
"m5/53-clin-stud-rep/535-rep-eff-safety-stud/nausea/nausea-sr15.pdf">
<title>nausea study report 15</title>
</leaf>
</m5-3-5-reports-of-efficacy-and-safety-studies>
</m5-3-clinical-study-reports>
</m5-clinical-study-reports>
</ectd:ectd>
Table 6-10
Element
Attribute
Description/Instructions
Example
<m3-2-s-drug-substance> Substance
This is an example of a section of the instance showing the submission of information about two drug
substances, one of which is supplied by two manufacturers:
<m3-2-body-of-data>
<m3-2-s-drug-substance substance = "acetaminophen" manufacturer = "my supplier">
<leaf ID=a123456 operation = "new" xlink:type = "simple" checksum-type=md5
checksum =
"e854d3002c02361fe54be926fd973401"
Page 6-11
xlink:href =
"m3/32-body-data/32s-drug-sub/acetaminophen-my-supplier/acetaminophen.pdf">
<title>acetaminophen my supplier data</title>
</leaf>
</m3-2-s-drug-substance>
<m3-2-s-drug-substance substance = "acetaminophen" manufacturer = "bulk company 2">
<leaf ID=a123457 operation = "new" xlink:type = "simple" checksum-type=md5
checksum =
"e854d3002402a61fe54be926fd973401"
xlink:href =
"m3/32-body-data/32s-drug-sub/acetaminophen-bulk-company-2/acetaminophen2.pdf">
<title>acetaminophen company 2 data</title>
</leaf>
</m3-2-s-drug-substance>
<m3-2-s-drug-substance substance = "codeine" manufacturer = "drug company 2">
<leaf ID=a123458 operation = "new" xlink:type = "simple" checksum-type=md5
checksum =
"e854d3002c02461fe54be926fd973401"
xlink:href =
"m3/32-body-data/32s-drug-sub/codeine-drug-company-2/codeine-quality-data.pdf">
<title>codeine data</title>
</leaf>
</m3-2-s-drug-substance>
</m3-2-body-of-data>
Multiple drug products use additional attributes associated with the <m3-2-p-drug-product> element to
allow unique combinations of the drug product name and dosage form to be submitted. The following table
shows the use of these attributes.
Table 6-11
Element
Attribute
Description/Instructions
Example
Wonder drug
This is an example of a section of the instance showing the submission of information about two drug
products:
<m3-2-body-of-data>
<m3-2-p-drug-product product-name = wonder drug dosageform=capsule-5mg>
<leaf ID=a123456 operation = "new" xlink:type = "simple" checksum-type=md5 checksum =
"e854d3002c02a61fe5cbe226fd973401"
xlink:href =
"m3/32-body-data/32p-drug-prod/capsule-5mg/32p1-desc-comp/description-andcomposition.pdf">
<title>wonder drug capsule product information</title>
</leaf>
</m3-2-p-drug-product>
<m3-2-p-drug-product product-name = wonder drug dosageform=tablet-5mg>
<leaf ID=a123457 operation = "new" xlink:type = "simple" checksum-type=md5 checksum =
"e854d3002c02a61fe5cbe926fd973401"
xlink:href =
"m3/32-body-data/32p-drug-prod/tablet-5mg/32p1-desc-comp/description-andcomposition.pdf">
<title>wonder drug tablet product data</title>
</leaf>
</m3-2-p-drug-product>
</m3-2-body-of-data>
Page 6-12
You should only extend the lowest level of defined elements. For example you can extend the
<m2-3-r-regional-information> element but not the <m2-3-quality-overall-summary> element
since the latter is not the lowest element defined in the table of contents.
Do not extend the element more than one level. For example, you should not extend <nodeextension> <title>special-fda-summary</title> </node-extension> with another <node-extension>.
The following is an example of a section of the eCTD instance in which an applicant extends the <m2-3-rregional-information> to provide specific regional information as requested by a regulatory authority. The
title element associated with the <node-extension> describes the extension. Alternatively, the regional
information in this example could have been provided as a <leaf> element under the <m2-3-r-regionalinformation> element without the use of a node extension.
<m2-common-technical-document-summaries>
<m2-3-quality-overall-summary>
<m2-3-r-regional-information>
<node-extension>
<title>special-fda-summary</title>
<leaf ID=a123456 operation = "new" xlink:type = "simple" xlink:href =
"m2/23-qos/fda/fda-extra-quality-sum.pdf">
<title> FDA extra quality summary </title>
</leaf>
</node-extension>
</m2-3-r-regional-information>
</m2-3-quality-overall-summary>
</m2-common-technical-document-summaries>
To update a file that has been submitted as an extended node, you should submit the replacement file using
exactly the same element and node extension information, including the <title> element for the <nodeextension>. This makes it possible for the regulatory authority to locate the original file and update its
status.
Page 6-13
Page 6-14
PDF
Adobe Portable Document Format (PDF) is a published format created by Adobe Systems Incorporated
(http://www.adobe.com). It is not necessary to use a product from Adobe or from any specific company to
produce PDF documents. PDF is accepted as a standard for documents defined in this specification. The
following recommendations support the creation of PDF files that agencies can review effectively. For any
specification of the Japanese version of Adobe Acrobat, or where Japanese characters will be in the file,
please refer to the regional guidance.
To ensure that PDF files can be accessed efficiently, PDF files should be no larger than 100 megabytes.
Optimize PDF files for fast web view.
Version
Agencies should be able to read all PDF files with version 4.0 or higher of the Acrobat Reader. Agencies
should not need any additional software to read and navigate the PDF files. However, review can be
facilitated through use of Adobe Acrobat since significantly more functionality is available in this product
than with Acrobat Reader.
Fonts
PDF viewing software automatically substitutes a font to display text if the font used to create the text is
unavailable on the reviewers computer. Font substitution can affect a documents appearance and
structure, and in some cases, the information conveyed by a document. Agencies cannot guarantee the
availability of any fonts except Times New Roman, Arial, and Courier and fonts supported in the Acrobat
product set itself. Therefore, all additional fonts used in the PDF files should be embedded to ensure that
those fonts would always be available to the reviewer. When embedding fonts, all characters for the font
should be embedded, not just a subset of the fonts being used in the document
Embedding fonts requires additional computer storage space. Three techniques to help limit the storage
space taken by embedding fonts include:
Limiting the number of fonts used in each document
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.
Page 7-1
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.
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 7-2
For lossless compression of color and grayscale images, use Zip/Flate (one technique with two names).
This is specified in Internet RFC 1950 and RFC 1951 (http://info.internet.isi.edu/innotes/rfc/files/rfc1950.txt).
For lossless compression of black and white images, use the CCITT Group 4 Fax compression
technique. It is specified as CCITT recommendations T.6 (1988) - Facsimile coding schemes and
coding control functions for Group 4 facsimile apparatus.
Paper documents containing hand-written notes should be scanned at 300 dpi. Hand-written notes should
be done in black ink for clarity.
For photographs, the image should be obtained with a resolution of 600 dpi. If black and white photos are
submitted, 8-bit grayscale images should be considered. If color photos are submitted, 24-bit RGB images
should be considered. A captured image should not be subjected to non-uniform scaling (i.e., sizing).
Gels and karyotypes should be scanned directly, rather than from photographs. Scanning should be at 600
dpi and 8-bit grayscale depth.
Plotter output graphics should be scanned or captured digitally at 300 dpi.
High-pressure liquid chromatography or similar images should be scanned at 300 dpi.
Applicants should validate the quality of the renditions.
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.
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.
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.
Page 7-5
Since ID is only needed for files referenced in a LEAF, changed ID back to IMPLIED for:
<!ENTITY % att " ID
ID #REQUIRED
xml:lang CDATA #IMPLIED">
<!ELEMENT node-extension (title, (leaf | node-extension)+)>
<!ATTLIST node-extension
ID ID #REQUIRED
xml:lang CDATA #IMPLIED>
Page 8-1
End of changes
-->
<!ENTITY % att " ID
ID #IMPLIED
xml:lang CDATA #IMPLIED">
<!-- ============================================================= -->
<!-- Top-level element -->
<!-- ============================================================= -->
<!ELEMENT ectd:ectd (m1-administrative-information-and-prescribing-information? , m2-commontechnical-document-summaries? , m3-quality? , m4-nonclinical-study-reports? , m5-clinical-studyreports?)>
<!ATTLIST ectd:ectd xmlns:ectd CDATA #FIXED 'http://www.ich.org/ectd'
xmlns:xlink CDATA #FIXED 'http://www.w3c.org/1999/xlink'
xml:lang CDATA #IMPLIED
dtd-version CDATA #FIXED '3.2' >
<!-- ============================================================= -->
<!-- Leaf content -->
<!-- ============================================================= -->
<!ELEMENT leaf (title , link-text?)>
<!ATTLIST leaf ID
ID #REQUIRED
application-version CDATA #IMPLIED
version
CDATA #IMPLIED
font-library
CDATA #IMPLIED
operation
(new | append | replace | delete ) #REQUIRED
modified-file
CDATA #IMPLIED
checksum
CDATA #REQUIRED
checksum-type
CDATA #REQUIRED
keywords
CDATA #IMPLIED
xmlns:xlink
CDATA #FIXED 'http://www.w3c.org/1999/xlink'
xlink:type
CDATA #FIXED 'simple'
xlink:role
CDATA #IMPLIED
xlink:href
CDATA #IMPLIED
xlink:show
(new | replace | embed | other | none ) #IMPLIED
xlink:actuate
(onLoad | onRequest | other | none ) #IMPLIED
xml:lang
CDATA #IMPLIED >
<!ELEMENT title (#PCDATA)>
<!ATTLIST title ID ID #IMPLIED >
<!ELEMENT link-text (#PCDATA | xref)*>
<!ATTLIST link-text ID ID #IMPLIED >
<!ELEMENT xref EMPTY>
<!ATTLIST xref ID
ID #REQUIRED
xmlns:xlink CDATA #FIXED 'http://www.w3c.org/1999/xlink'
xlink:type CDATA #FIXED 'simple'
xlink:role CDATA #IMPLIED
xlink:title CDATA #REQUIRED
xlink:href CDATA #REQUIRED
xlink:show (new | replace | embed | other | none ) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none ) #IMPLIED >
<!ELEMENT node-extension (title , (leaf | node-extension)+)>
<!ATTLIST node-extension ID
Page 8-2
ID
#IMPLIED
Page 8-3
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Page 8-7
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Page 8-12
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 computerreadable 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 platformindependent manner.
Page 9-3
SECTION 14
Overview
Examples
How to ensure success
eCTD Submission
Use of Elements
Leaf Titles
xlink:href
Extra files
Failing to Repeat Complete Directory Structure on
each media component in a set
Submissions
Company Name
Drug Name
Submission Type
Submission Date
Application Number
Sequence Number
No Alpha Characters
No - , or other punctuation
No spaces
Six Numbers pad left 0 if 5 digits are given
Except
The MD5 Checksum value is provided in a one-line
text file index-md5.txt - in each sequence number
directory
To Summarize
Ensuring Success
Submit a Sample eCTD prior to your real
eCTD (contact info next slide)
Follow the specifications and guidances
References
SECTION 15
Session 317
Medical/Scientific Writing Track
ISS/ISE:
Where Do They Fit
in the CTD/eCTD?
Learning objectives
http://www.ich.org
INTERNATIONAL CONFERENCE ON
HARMONIS/ZATION
of
Technical Requirements
for the Registration of
Pharmaceuticals for Human Use
ICH
A Unique Approach
ICH Objectives
Harmonized Guidelines
2.3
2.6
2.4
2.2
2.7
2.5
2.2 Introduction
Module 3
Module 4
Module 5 2.7 Clinical Summary
Nonclinical
Clinical
Quality
Study Reports Study Reports Source: ICH Implementation Coordination Group
3.0
4.0
5.0
Module 2
2.1
1.0
Module 1
July 1, 2003
ANSWER
Todays Session
Gary Gensinger
SECTION 16
Demo
Overview
Data definitions
Study data
Analysis datasets
PDF files that include all study data collected for an individual subject
organized by time
Subject profiles
Why Standards?
Standards allow:
Standards provide:
Other
Government
Terminology Standards
Initiatives
10
Content Standards
Management of data
Evaluate
11
12
13
Development of EasyView
Allows reviewers to
Development
Data model
Implementation requirements
Development
Validation of data
Parsing of data into database
Development
Management of Data
Demo
16
17
Submission
Data
Tabulations
Data listings
Profiles
Analysis datasets
Programs
Definition
Repository
Electronic
Document Room
Review
Stat/transfer
Acrobat
Electronic Datasets
18
Dataset files
Submission
Data
Std Tabulations
Data listings
Profiles
Analysis datasets
Programs
Definition
Repository
Tools
Electronic
Document Room
Review
19
Dataset files
Profile
Stat/transfer
Acrobat
Submission
Data
Std Tabulations
Data listings
Profiles
Analysis datasets
Programs
Definition
Repository
Tools
Data Tables
Electronic
Document Room
Dataset files
Review
20
Tabulations
Data listing
Profile
Stat/transfer
Acrobat
Submission
Data
Std Tabulations
Data listings
Profiles
Analysis datasets
Programs
Definition
Repository
Tools
JANUS
Study Data
Repository
Electronic
Document Room
Dataset files
Review
21
Tabulations
Data listing
Profile
Stat/transfer
Acrobat
Submission
Data
Std Tabulations
Data listings
Profiles
Std analysis methods
Definition
Repository
Tools
JANUS
Study Data
Repository
Electronic
Document Room
Review
Datasets
Profile
22
SECTION 17
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
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if that approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
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:
The information provided here reflects the consensus of the ICH parties. The annex will be
incorporated in FDAs next revision of the M4 guidance.
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.
2.1
2.2
Note 1
2.3
2.3.P
Note 3
2.3.A
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
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.1
2.3.A.2
2.3.A.3
2.3.R
2.4
2.5
2.6
2.7
2.6.1
2.6.2
2.6.3
2.6.4
2.6.5
2.6.6
2.6.7
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
Note 1
3.1
3.2
The TOC is only called for in the paper version of the CTD;
there is no entry needed for the eCTD
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
3.2.P
Note 3
3.2.P.1
3.2.P.2
3.2.P.2.1
3.2.P.2.2
Note 4
Note 4
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
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
Note 5
3.2.R
3.3
One file
Note 6
per reference
Key
Documents rolled up to this level are not considered appropriate
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.
4.1
4.2
The TOC is only called for in the paper version of the CTD; there
is no entry needed for the eCTD
4.2.1
4.2.2
4.2.3
4.2.1.1
4.2.1.2
4.2.1.3
4.2.1.4
4.2.2.1
4.2.2.2
4.2.2.3
4.2.2.4
4.2.2.5
4.2.2.6
4.2.2.7
4.2.3.1
4.2.3.2
4.2.3.3
4.2.3.4
4.2.3.5
4.2.3.6
4.2.3.7
4.3
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
4.2.3.3.1
4.2.3.3.2
4.2.3.4.1
4.2.3.4.2
4.2.3.4.3
4.2.3.5.1
4.2.3.5.2
4.2.3.5.3
4.2.3.5.4
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
4.2.3.7.1
4.2.3.7.2
4.2.3.7.3
4.2.3.7.4
4.2.3.7.5
4.2.3.7.6
4.2.3.7.7
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Note 1
Studies
Key
Documents rolled up to this level are not considered appropriate
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
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
5.3
5.3.1
5.3.2
5.3.3
5.3.4
5.3.5
5.4
Note 2
5.3.6
5.3.7
One file per
reference Note 3
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
5.3.2.1
Studies
Note 1
5.3.2.2
Studies
Note 1
5.3.2.3
Studies
Note 1
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
5.3.4.1
Studies
Note 1
5.3.4.2
Studies
Note 1
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
Note 1
Studies
Note 1
Key
Documents rolled up to this level are not considered appropriate
One document can be submitted at this level
One or multiple documents 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.
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
10
SECTION 18
This section includes code for the XML submission that needs to be created and
validated according to the XML eCTD DTD standard.
End of changes
-->
<!ENTITY % att " ID
ID #IMPLIED
xml:lang CDATA #IMPLIED">
<!-============================================================= -->
<!-- Top-level element -->
<!-============================================================= -->
<!ELEMENT ectd:ectd (m1-administrative-information-and-prescribing-information?,
m2-common-technical-document-summaries?, m3-quality?, m4-nonclinical-studyreports?, 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"
xml:lang CDATA #IMPLIED
dtd-version CDATA #FIXED "3.2"
>
<!-============================================================= -->
<!-- Leaf content -->
<!-============================================================= -->
<!ELEMENT leaf (title, link-text?)>
<!ATTLIST leaf
ID ID #REQUIRED
application-version CDATA #IMPLIED
version CDATA #IMPLIED
font-library CDATA #IMPLIED
operation (new | append | replace | delete) #REQUIRED
modified-file CDATA #IMPLIED
checksum CDATA #REQUIRED
checksum-type CDATA #REQUIRED
keywords CDATA #IMPLIED
xmlns:xlink CDATA #FIXED "http://www.w3c.org/1999/xlink"
xlink:type CDATA #FIXED "simple"
xlink:role CDATA #IMPLIED
xlink:href CDATA #IMPLIED
>
<!ELEMENT title (#PCDATA)>
<!ATTLIST title
ID ID #IMPLIED
>
<!ELEMENT link-text (#PCDATA | xref)*>
<!ATTLIST link-text
ID ID #IMPLIED
>
<!ELEMENT xref EMPTY>
<!ATTLIST xref
ID ID #REQUIRED
xmlns:xlink CDATA #FIXED "http://www.w3c.org/1999/xlink"
xlink:type CDATA #FIXED "simple"
xlink:role CDATA #IMPLIED
xlink:title CDATA #REQUIRED
xlink:href CDATA #REQUIRED
xlink:show (new | replace | embed | other | none) #IMPLIED
xlink:actuate (onLoad | onRequest | other | none) #IMPLIED
>
<!ELEMENT node-extension (title, (leaf | node-extension)+)>
<!ATTLIST node-extension
ID ID #IMPLIED
xml:lang CDATA #IMPLIED
>
<!-============================================================= -->
<!-- CTD Backbone structures -->
<!-============================================================= -->
<!ELEMENT m1-administrative-information-and-prescribing-information (leaf*)>
<!ATTLIST m1-administrative-information-and-prescribing-information
%att;
>
<!ELEMENT m2-common-technical-document-summaries (leaf*, m2-2-introduction?,
m2-3-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-drugsubstance*, m2-3-p-drug-product*, m2-3-a-appendices?, m2-3-r-regional-information?)>
<!ATTLIST m2-3-quality-overall-summary
%att;
>
<!ELEMENT m2-3-introduction ((leaf | node-extension)*)>
<!ATTLIST m2-3-introduction
%att;
>
<!ELEMENT m2-3-s-drug-substance ((leaf | node-extension)*)>
<!ATTLIST m2-3-s-drug-substance
%att;
substance CDATA #REQUIRED
manufacturer CDATA #REQUIRED
>
<!ELEMENT m2-3-p-drug-product ((leaf | node-extension)*)>
<!ATTLIST m2-3-p-drug-product
%att;
product-name CDATA #IMPLIED
dosageform CDATA #IMPLIED
manufacturer CDATA #IMPLIED
>
<!ELEMENT m2-3-a-appendices ((leaf | node-extension)*)>
<!ATTLIST m2-3-a-appendices
%att;
>
<!ELEMENT m2-3-r-regional-information ((leaf | node-extension)*)>
<!ATTLIST m2-3-r-regional-information
%att;
>
<!ELEMENT m2-4-nonclinical-overview ((leaf | node-extension)*)>
<!ATTLIST m2-4-nonclinical-overview
%att;
>
<!ELEMENT m2-5-clinical-overview ((leaf | node-extension)*)>
<!ATTLIST m2-5-clinical-overview
%att;
>
<!ELEMENT m2-6-nonclinical-written-and-tabulated-summaries (leaf*, m2-6-1introduction?, m2-6-2-pharmacology-written-summary?, m2-6-3-pharmacologytabulated-summary?, m2-6-4-pharmacokinetics-written-summary?, m2-6-5pharmacokinetics-tabulated-summary?, m2-6-6-toxicology-written-summary?, m2-6-7toxicology-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)*)>
<!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-biopharmaceuticstudies-and-associated-analytical-methods?, m2-7-2-summary-of-clinical-pharmacologystudies?, 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-analyticalmethods ((leaf | node-extension)*)>
<!ATTLIST m2-7-1-summary-of-biopharmaceutic-studies-and-associated-analyticalmethods
%att;
>
<!ELEMENT m2-7-2-summary-of-clinical-pharmacology-studies ((leaf | nodeextension)*)>
<!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-2manufacture?, m3-2-s-3-characterisation?, m3-2-s-4-control-of-drug-substance?, m3-2-s5-reference-standards-or-materials?, m3-2-s-6-container-closure-system?, m3-2-s-7stability?)>
<!ATTLIST m3-2-s-drug-substance
%att;
substance CDATA #REQUIRED
manufacturer CDATA #REQUIRED
>
<!ELEMENT m3-2-s-1-general-information (leaf*, m3-2-s-1-1-nomenclature?, m3-2-s1-2-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-2-2description-of-manufacturing-process-and-process-controls?, m3-2-s-2-3-control-ofmaterials?, m3-2-s-2-4-controls-of-critical-steps-and-intermediates?, m3-2-s-2-5-processvalidation-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;
>
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((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 | nodeextension)*)>
<!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 | nodeextension)*)>
<!ATTLIST m3-2-s-2-5-process-validation-and-or-evaluation
%att;
>
<!ELEMENT m3-2-s-2-6-manufacturing-process-development ((leaf | nodeextension)*)>
<!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-andother-characteristics?, m3-2-s-3-2-impurities?)>
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%att;
>
<!ELEMENT m3-2-s-3-1-elucidation-of-structure-and-other-characteristics ((leaf | nodeextension)*)>
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%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?, m32-s-4-2-analytical-procedures?, m3-2-s-4-3-validation-of-analytical-procedures?, m3-2-s4-4-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;
>
<!ELEMENT m3-2-s-4-2-analytical-procedures ((leaf | node-extension)*)>
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%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;
>
>
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%att;
>
<!ELEMENT m3-2-p-4-6-novel-excipients ((leaf | node-extension)*)>
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%att;
>
<!ELEMENT m3-2-p-5-control-of-drug-product (leaf*, m3-2-p-5-1-specifications?, m32-p-5-2-analytical-procedures?, m3-2-p-5-3-validation-of-analytical-procedures?, m3-2p-5-4-batch-analyses?, m3-2-p-5-5-characterisation-of-impurities?, m3-2-p-5-6justification-of-specifications?)>
<!ATTLIST m3-2-p-5-control-of-drug-product
%att;
>
<!ELEMENT m3-2-p-5-1-specifications ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-1-specifications
%att;
>
<!ELEMENT m3-2-p-5-2-analytical-procedures ((leaf | node-extension)*)>
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%att;
>
<!ELEMENT m3-2-p-5-3-validation-of-analytical-procedures ((leaf | node-extension)*)>
<!ATTLIST m3-2-p-5-3-validation-of-analytical-procedures
%att;
>
<!ELEMENT m3-2-p-5-4-batch-analyses ((leaf | node-extension)*)>
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%att;
>
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%att;
>
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%att;
>
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%att;
>
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%att;
>
<!ELEMENT m3-2-p-8-stability (leaf*, m3-2-p-8-1-stability-summary-and-conclusion?,
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<!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-2adventitious-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
dosageform CDATA #IMPLIED
product-name CDATA #IMPLIED
>
<!ELEMENT m3-2-a-2-adventitious-agents-safety-evaluation ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-2-adventitious-agents-safety-evaluation
%att;
manufacturer CDATA #IMPLIED
substance CDATA #IMPLIED
dosageform CDATA #IMPLIED
product-name CDATA #IMPLIED
>
<!ELEMENT m3-2-a-3-excipients ((leaf | node-extension)*)>
<!ATTLIST m3-2-a-3-excipients
%att;
>
<!ELEMENT m3-2-r-regional-information ((leaf | node-extension)*)>
<!ATTLIST m3-2-r-regional-information
%att;
>
<!ELEMENT m3-3-literature-references ((leaf | node-extension)*)>
<!ATTLIST m3-3-literature-references
%att;
>
<!ELEMENT m4-nonclinical-study-reports (leaf*, m4-2-study-reports?, m4-3-literaturereferences?)>
<!ATTLIST m4-nonclinical-study-reports
%att;
>
<!ELEMENT m4-2-study-reports (leaf*, m4-2-1-pharmacology?, m4-2-2pharmacokinetics?, m4-2-3-toxicology?)>
<!ATTLIST m4-2-study-reports
%att;
>
<!ELEMENT m4-2-1-pharmacology (leaf*, m4-2-1-1-primary-pharmacodynamics?, m42-1-2-secondary-pharmacodynamics?, m4-2-1-3-safety-pharmacology?, m4-2-1-4pharmacodynamic-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-andvalidation-reports?, m4-2-2-2-absorption?, m4-2-2-3-distribution?, m4-2-2-4metabolism?, m4-2-2-5-excretion?, m4-2-2-6-pharmacokinetic-drug-interactions?, m4-22-7-other-pharmacokinetic-studies?)>
<!ATTLIST m4-2-2-pharmacokinetics
%att;
>
<!ELEMENT m4-2-2-1-analytical-methods-and-validation-reports ((leaf | nodeextension)*)>
<!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?, m4-2-3-2repeat-dose-toxicity?, m4-2-3-3-genotoxicity?, m4-2-3-4-carcinogenicity?, m4-2-3-5reproductive-and-developmental-toxicity?, m4-2-3-6-local-tolerance?, m4-2-3-7-othertoxicity-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 m4-2-3-5-3-prenatal-and-postnatal-development-including-maternalfunction ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-3-prenatal-and-postnatal-development-including-maternalfunction
%att;
>
<!ELEMENT m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosedand-or-further-evaluated ((leaf | node-extension)*)>
<!ATTLIST m4-2-3-5-4-studies-in-which-the-offspring-juvenile-animals-are-dosed-andor-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?, m4-2-37-2-immunotoxicity?, m4-2-3-7-3-mechanistic-studies?, m4-2-3-7-4-dependence?, m4-23-7-5-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;
>
<!ELEMENT m4-3-literature-references ((leaf | node-extension)*)>
<!ATTLIST m4-3-literature-references
%att;
>
<!ELEMENT m5-clinical-study-reports (leaf*, m5-2-tabular-listing-of-all-clinicalstudies?, 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-biopharmaceuticstudies?, m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-humanbiomaterials?, m5-3-3-reports-of-human-pharmacokinetics-pk-studies?, m5-3-4-reportsof-human-pharmacodynamics-pd-studies?, m5-3-5-reports-of-efficacy-and-safetystudies*, m5-3-6-reports-of-postmarketing-experience?, m5-3-7-case-report-forms-andindividual-patient-listings?)>
<!ATTLIST m5-3-clinical-study-reports
%att;
>
<!ELEMENT m5-3-1-reports-of-biopharmaceutic-studies (leaf*, m5-3-1-1bioavailability-study-reports?, m5-3-1-2-comparative-ba-and-bioequivalence-studyreports?, m5-3-1-3-in-vitro-in-vivo-correlation-study-reports?, m5-3-1-4-reports-ofbioanalytical-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 | nodeextension)*)>
<!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 | nodeextension)*)>
<!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-humanstudies ((leaf | node-extension)*)>
<!ATTLIST m5-3-1-4-reports-of-bioanalytical-and-analytical-methods-for-humanstudies
%att;
>
<!ELEMENT m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-humanbiomaterials (leaf*, m5-3-2-1-plasma-protein-binding-study-reports?, m5-3-2-2-reportsof-hepatic-metabolism-and-drug-interaction-studies?, m5-3-2-3-reports-of-studies-usingother-human-biomaterials?)>
<!ATTLIST m5-3-2-reports-of-studies-pertinent-to-pharmacokinetics-using-humanbiomaterials
%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
((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 | nodeextension)*)>
<!ATTLIST m5-3-2-3-reports-of-studies-using-other-human-biomaterials
%att;
>
<!ELEMENT m5-3-3-reports-of-human-pharmacokinetics-pk-studies (leaf*, m5-3-3-1healthy-subject-pk-and-initial-tolerability-study-reports?, m5-3-3-2-patient-pk-andinitial-tolerability-study-reports?, m5-3-3-3-intrinsic-factor-pk-study-reports?, m5-3-3-4extrinsic-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 | nodeextension)*)>
<!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*, m5-3-4-1healthy-subject-pd-and-pk-pd-study-reports?, m5-3-4-2-patient-pd-and-pk-pd-studyreports?)>
<!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 | nodeextension)*)>
<!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-studyreports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication?, m5-3-5-2study-reports-of-uncontrolled-clinical-studies?, m5-3-5-3-reports-of-analyses-of-datafrom-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-theclaimed-indication ((leaf | node-extension)*)>
<!ATTLIST m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-theclaimed-indication
%att;
>
<!ELEMENT m5-3-5-2-study-reports-of-uncontrolled-clinical-studies ((leaf | nodeextension)*)>
<!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 | nodeextension)*)>
<!ATTLIST m5-3-7-case-report-forms-and-individual-patient-listings
%att;
>
<!ELEMENT m5-4-literature-references ((leaf | node-extension)*)>
<!ATTLIST m5-4-literature-references
%att;
>
SECTION 19
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.
<!ATTLIST m1-3-2-field-copy-certification
%att;
>
<!-- ===================== DEBARMENT CERTIFICATION
================== -->
<!ELEMENT m1-3-3-debarment-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-3-debarment-certification
%att;
>
<!-- ===================== FINANCIAL CERTIFICATION DISCLOSURE
======= -->
<!ELEMENT m1-3-4-financial-certification-disclosure ((leaf | node-extension)*)>
<!ATTLIST m1-3-4-financial-certification-disclosure
%att;
>
<!-- ===================== PATENT EXCLUSIVITIY
====================== -->
<!ELEMENT m1-3-5-patent-exclusivity (m1-3-5-1-patent-information*,
m1-3-5-2-patent-certification*, m1-3-5-3-exclusivity-request*)>
<!ATTLIST m1-3-5-patent-exclusivity
%att;
>
<!ELEMENT m1-3-5-1-patent-information ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-1-patent-information
%att;
>
<!ELEMENT m1-3-5-2-patent-certification ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-2-patent-certification
%att;
>
<!ELEMENT m1-3-5-3-exclusivity-request ((leaf | node-extension)*)>
<!ATTLIST m1-3-5-3-exclusivity-request
%att;
>
<!-- ===================== REFERENCES
=============================== -->
<!ELEMENT m1-4-references (m1-4-1-letter-authorization*,
m1-4-2-statement-right-reference*,
m1-4-3-list-of-authorized-persons-to-incorporate-by-reference*,
m1-4-4-cross-reference-other-applications*)>
<!ATTLIST m1-4-references
%att;
>
<!ELEMENT m1-4-1-letter-authorization ((leaf | node-extension)*)>
<!ATTLIST m1-4-1-letter-authorization
%att;
>
<!ELEMENT m1-4-2-statement-right-reference ((leaf | node-extension)*)>
<!ATTLIST m1-4-2-statement-right-reference
%att;
>
<!ELEMENT m1-4-3-list-of-authorized-persons-to-incorporate-by-reference ((leaf |
node-extension)*)>
<!ATTLIST m1-4-3-list-of-authorized-persons-to-incorporate-by-reference
%att;
>
<!ELEMENT m1-4-4-cross-reference-other-applications ((leaf | node-extension)*)>
<!ATTLIST m1-4-4-cross-reference-other-applications
%att;
>
<!-- ===================== APPLICATION STATUS
======================= -->
<!ELEMENT m1-5-application-status (m1-5-1-withdrawal-request*,
m1-5-2-inactivation-request*, m1-5-3-reactivation-request*,
m1-5-4-reinstatement-request*, m1-5-5-withdrawal-unapproved-nda*,
m1-5-6-withdrawal-of-listed-drug*,
m1-5-7-request-withdrawal-application-approval*)>
<!ATTLIST m1-5-application-status
%att;
>
<!ELEMENT m1-5-1-withdrawal-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-1-withdrawal-request
%att;
>
<!ELEMENT m1-5-2-inactivation-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-2-inactivation-request
%att;
>
<!ELEMENT m1-5-3-reactivation-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-3-reactivation-request
%att;
>
<!ELEMENT m1-5-4-reinstatement-request ((leaf | node-extension)*)>
<!ATTLIST m1-5-4-reinstatement-request
%att;
>
<!ELEMENT m1-5-5-withdrawal-unapproved-nda ((leaf | node-extension)*)>
<!ATTLIST m1-5-5-withdrawal-unapproved-nda
%att;
>
<!ELEMENT m1-5-6-withdrawal-of-listed-drug ((leaf | node-extension)*)>
<!ATTLIST m1-5-6-withdrawal-of-listed-drug
%att;
>
<!ELEMENT m1-5-7-request-withdrawal-application-approval ((leaf |
node-extension)*)>
<!ATTLIST m1-5-7-request-withdrawal-application-approval
%att;
>
<!-- ===================== MEETINGS
================================= -->
<!ELEMENT m1-6-meetings (m1-6-1-meeting-request*,
m1-6-2-meeting-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;
>
<!-- ===================== FAST TRACK
=============================== -->
<!ELEMENT m1-7-fast-track (m1-7-1-fast-track-designation-request*,
m1-7-2-fast-track-designation-withdrawal-request*, m1-7-3-rolling-review-request*)>
<!ATTLIST m1-7-fast-track
%att;
>
<!ELEMENT m1-7-1-fast-track-designation-request ((leaf | node-extension)*)>
<!ATTLIST m1-7-1-fast-track-designation-request
%att;
>
<!ELEMENT m1-7-2-fast-track-designation-withdrawal-request ((leaf |
node-extension)*)>
<!ATTLIST m1-7-2-fast-track-designation-withdrawal-request
%att;
>
<!ELEMENT m1-7-3-rolling-review-request ((leaf | node-extension)*)>
<!ATTLIST m1-7-3-rolling-review-request
%att;
>
<!-- ===================== SPECIAL PROTOCOL ASSESSMENT REQUEST
====== -->
<!ELEMENT m1-8-special-protocol-assessment-request (m1-8-1-clinical-study*,
m1-8-2-carcinogenicity-study*, m1-8-3-stability-study*)>
<!ATTLIST m1-8-special-protocol-assessment-request
%att;
>
<!ELEMENT m1-8-1-clinical-study ((leaf | node-extension)*)>
<!ATTLIST m1-8-1-clinical-study
%att;
>
<!ELEMENT m1-8-2-carcinogenicity-study ((leaf | node-extension)*)>
<!ATTLIST m1-8-2-carcinogenicity-study
%att;
>
<!ELEMENT m1-8-3-stability-study ((leaf | node-extension)*)>
<!ATTLIST m1-8-3-stability-study
%att;
>
<!-- ===================== PEDIATRIC ADMINISTRATIVE INFORMATION
===== -->
<!ELEMENT m1-9-pediatric-administrative-information
(m1-9-1-request-waiver-pediatric-studies*,
m1-9-2-request-deferral-pediatric-studies*,
m1-9-3-request-pediatric-exclusivity-determination*,
m1-9-4-proposed-pediatric-study-request-amendments*,
m1-9-5-proposal-written-agreement*,
m1-9-6-other-correspondence-regarding-pediatric-exclusivity-study-plans*)>
<!ATTLIST m1-9-pediatric-administrative-information
%att;
>
<!ELEMENT m1-9-1-request-waiver-pediatric-studies ((leaf | node-extension)*)>
<!ATTLIST m1-9-1-request-waiver-pediatric-studies
%att;
>
<!ELEMENT m1-9-2-request-deferral-pediatric-studies ((leaf | node-extension)*)>
<!ATTLIST m1-9-2-request-deferral-pediatric-studies
%att;
>
<!ELEMENT m1-9-3-request-pediatric-exclusivity-determination ((leaf |
node-extension)*)>
<!ATTLIST m1-9-3-request-pediatric-exclusivity-determination
%att;
>
<!ELEMENT m1-9-4-proposed-pediatric-study-request-amendments ((leaf |
node-extension)*)>
<!ATTLIST m1-9-4-proposed-pediatric-study-request-amendments
%att;
>
<!ELEMENT m1-9-5-proposal-written-agreement ((leaf | node-extension)*)>
<!ATTLIST m1-9-5-proposal-written-agreement
%att;
>
<!ELEMENT m1-9-6-other-correspondence-regarding-pediatric-exclusivity-study-plans
((leaf | node-extension)*)>
<!ATTLIST m1-9-6-other-correspondence-regarding-pediatric-exclusivity-study-plans
%att;
>
<!-- ===================== DISPUTE RESOLUTION
======================= -->
<!ELEMENT m1-10-dispute-resolution (m1-10-1-request-for-dispute-resolution*,
m1-10-2-correspondence-related-to-dispute-resolution*)>
<!ATTLIST m1-10-dispute-resolution
%att;
>
<!ELEMENT m1-10-1-request-for-dispute-resolution ((leaf | node-extension)*)>
<!ATTLIST m1-10-1-request-for-dispute-resolution
%att;
>
<!ELEMENT m1-10-2-correspondence-related-to-dispute-resolution ((leaf |
node-extension)*)>
<!ATTLIST m1-10-2-correspondence-related-to-dispute-resolution
%att;
>
<!-- ===================== INFORMATION ADMENDMENT
=================== -->
<!ELEMENT m1-11-information-amendment
(m1-11-1-quality-information-amendment*,
m1-11-2-safety-information-amendment*,
m1-11-3-efficacy-information-amendment*,
m1-11-4-multiple-module-information-amendments*)>
<!ATTLIST m1-11-information-amendment
%att;
>
<!ELEMENT m1-11-1-quality-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-1-quality-information-amendment
%att;
>
<!ELEMENT m1-11-2-safety-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-2-safety-information-amendment
%att;
>
<!ELEMENT m1-11-3-efficacy-information-amendment ((leaf | node-extension)*)>
<!ATTLIST m1-11-3-efficacy-information-amendment
%att;
>
<!ELEMENT m1-11-4-multiple-module-information-amendments ((leaf |
node-extension)*)>
<!ATTLIST m1-11-4-multiple-module-information-amendments
%att;
>
<!-- ===================== OTHER CORRESPONDENCE
===================== -->
<!ELEMENT m1-12-other-correspondence (m1-12-1-pre-ind-correspondence*,
m1-12-2-request-charge*, m1-12-3-notification-charging-under-treatment-ind*,
m1-12-4-request-comments-advice-ind*, m1-12-5-request-waiver*,
m1-12-6-exemption-informed-consent-emergency-research*,
m1-12-7-public-disclosure-statement-emergency-care-research*,
m1-12-8-correspondence-regarding-emergency-care-research*,
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;
>
<!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;
>
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;
>
SECTION 20
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.
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
21 CFR 314.50
(c)(2)(viii)
Comment
Not a U.S.
requirement, but
recommended by
ICH guidance
21 CFR 314.50
(d)(5)(v)
21 CFR 314.50
(d)(5)(vi)
Integrated Summary
of Efficacy
Integrated Summary
of Safety
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
Version 1.0
Summary of Changes
Initial version
Non proportional
Serif
Font name
AdobeSansMM (Adobe Sans Multiple Master)
Arial BolitaMT (Arial Bold Italic (From Monotype))
ArialBolMT
(Arial Bold Monotype)
ArialtaMT
Arial Italic (Monotype)
ArialMT
Arial (Monotype)
Couri (Courier)
CouriBol (Courier Bold)
CourriBolObl (Courier Bold Oblique)
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)
Version 1.0
TimesNewRoman
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 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
Resolution
300 dpi (black ink)
300 dpi
600 dpi (8 bit gray scale)
600 dpi (24 bit RGB)
600 dpi (8 bit grayscale depth)
300 dpi
Zip/Flate (one technique with two names) for lossless compression of color and grayscale
images is specified in Internet RFC 1950 and RFC 1951.
Version 1.0
SECTION 22
Summary of Changes
Original version
Correction of typographical error in Type of Media table
Format
3.5 inch 1.44 MB
CD-R Joliet Specification
DVD-RAM
DVD-R
DVD+R
DVD+/-R
35/70 or 40/80 DLT tapes
using
Veritas backup exec,
Win2000 native backup.
do not use compression
LTO 1 (100/200 GB) or LTO
2
Size
Up to 14.4 MB (10 disks)
Up to 3 GB (1- 5 CDs)
Up to 45 GB (1 to 6 DVDs)
No limit
No limit
SECTION 23
Standards and
Successful Document
Creation
Module 2 Summaries
caBIG https://cabig.nci.nih.gov
http://www.fda.gov/cder/regulatory/ersr/2002_0-6_19_standards/index.htm
Remember!
Good
Bad
Provide Bookmarks
with Intuitive Names
Bookmarks
Application C
Application B
2.7.3 70 pages
2.7.4 86 pages
Application A
ISS/ISE Experiences
Contact Information
SECTION 24
503
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
The Backdrop
504
Problems
505
506
507
508
509
The ICH CTD recommends smaller granular files instead of single large files
encompassing all aspects of the study report
Each section can result in the creation of one or more files containing
pertinent information
The globally acknowledged values are not included in the eCTD DTD
Individual headings for each section are not included in the eCTD DTD
510
Interim Fix
511
E3 granularity sections
512
mouse
rat
rabbit
other-rodent
dog
nonhuman-primate
other-nonrodentmammal
nonmammal
oral
intravenous
intramuscular
intraperitoneal
subcutaneous
inhalation
topical
Routes of
Administration
513
placebo
no-treatment-control
dose-response-without-control
active-control-without-placebo
external-control
514
synopsis
study-report-body
protocol-or-amendment
sample-case-report-form
iec-erb-consent-form-list
list-description-investigator-site
515
Data Tabulation
files
Case Report
Form files
Protocols file
Synopsis file
Study Report
dose-responsewithoutcontrol
intravenous
Mouse
topical
Rat
placebo
Rabbit
notreatment
-control
oral
dose-responsewithoutcontrol
intravenous
Mouse
Data File 1
Data File 2
CRF 1 Site 1
CRF n Site n
Protocols file
Synopsis file
Study
StudyReport
Report
data-tabulation-dataset
data-tabulation-dataset
case-report-forms
site n
case-report-forms
site 1
protocol-or-amendment
study-report-body
synopsis
Study Report
517
synopsis
Mouse
data-tabulation-dataset
case-report-forms
site 1
case-report-forms
site n
data-tabulation-dataset
protocol-or-amendment
dose-responsewithoutcontrol
Document Id
study-report-body
intravenous
518
dataset.XPT
Leaf
CRF.pdf
Leaf
Protocol.pdf
Stf-study-report.xml
Leaf
dataset.XPT
N
CRF.pdf
Leaf
Leaf
519
Leaf
Synopsis.pdf
Leaf
Leaf
520
999999/
0000/
m5/
53-clin-study-report/
535-rep-effic-safety-study/
Claimed indication/
5351-study-report-contrib/
xxx394-90-04/
Workshop Sample
521
../../../../../../index.xml#ID382213
Dataset2.xpt
../../../../../../index.xml#ID246080
Dataset1.xpt
../../../../../../index.xml#ID387525
CRFnsiten.pdf
../../../../../../index.xml#ID820214
CRF1site01.pdf
../../../../../../index.xml#ID350438b
XXX394-90-04protocol.pdf
../../../../../../index.xml#ID350438a
XXX394-90-04body-of-report.pdf
../../../../../../index.xml#ID350438
XXX394-90-04synopsis.pdf
Workshop Sample
522
Note: ../../../ means to use the relative location of the STF file
523
<document-identifier>
<title> A Parallel Group, PlaceboControlled, Modified Double-Blind, DoseRanging 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>
524
525
<doc-content >
<property name="leaf-id" info-type=fda>
../../../../../../index.xml#ID350438a
</property>
<file-tag name="study-report-body
info-type=ich-e3/>
</doc-content>
526
<doc-content >
<property name="leaf-id" info-type=fda>
../../../../../../index.xml#ID820214
</property>
<property name=site-identifier
info-type=fda>1</property>
<file-tag name="case-report-forms
info-type=ich-e3/>
</doc-content>
527
<doc-content >
<property name="leaf-id" info-type=fda>
../../../../../../index.xml#ID387525
</property>
<property name=site-identifier
info-type=fda>n</property>
<file-tag name="case-report-forms
info-type=ich-e3/>
</doc-content>
528
<doc-content >
<property name="leaf-id" info-type=fda>
../../../../../../index.xml#ID246080
</property>
<file-tag name="analysis-dataset
info-type=ich-e3/>
</doc-content>
</document>
</ectd:study>
Add the tags for the analysis datasets and close the STF
File
529
530
grouped by species
531
532
http://www.fda.gov/cder/regulatory/ersr/ectd.htm
Order of Display
533
Note: the above is defined to mean group the study files under the
heading Controlled based on the value placebo of the type-ofcontrol 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.
Clinical
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, PlaceboControlled, Modified Double-Blind, Dose-Ranging Study
with XXX 394 in Patients with SLE
Synopsis
synopsis leaf-id ../../../../../../index.xml#ID350438
Concept
534
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
Concept - 2
535
Concept - 3
536
Data Tabulation
Data tabulation datasets
data-tabulation leaf-id ../../../../../../index.xml#ID246080
data-tabulation leaf-id ../../../../../../index.xml#ID382213
data-tabulation leaf-id ../../../../../../index.xml#ID547320
data-tabulation leaf-id ../../../../../../index.xml#ID521586
data-tabulation leaf-id ../../../../../../index.xml#ID49242
Data Definitions
tabulation-definition leaf-id ../../../../../../index.xml#ID861459
Concept - 4
537
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
Analysis Datasets
Concept - 5
538
SECTION 25
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" ?>
<!-- ectd
util/ectd-2-0.xsl
version 2.0
transformation of the backbone from xml to html
Yokohama, November 17, 2004
-->
- <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:
<xsl:value-of select="@excipient" />
]
</xsl:if>
</font>
</li>
<xsl:apply-templates />
</ul>
</xsl:template>
- <xsl:template match="leaf">
- <ul type="square">
- <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">
- <ul type="square">
- <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
Page 2
2/6/2007
Part 5
Training
SECTION 26
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).
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
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:
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.
Windows 95
12 MB RAM
16 MB RAM
Lesson 1 NEDAT
Presentation
Please use the blank lines to take notes during the presentation.
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Slide 1
NDA Electronic Data Analysis
Training (NEDAT)
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CDER/OIT Training
Please Sign-In Before Seating and
Make Sure to Logon with Your
Username
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Slide 2
NEDAT Overview
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Slide 3
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Data analysis
Publicly available information is on the
Internet
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Slide 4
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Archivable
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defacto Standard
Free viewer (The SAS System Viewer)
User-friendly navigation
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Slide 5
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NDA Discipline Folder:
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Slide 6
Each Datasets folder contains
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Slide 7
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Each Study Folder Contains:
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Slide 8
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Table/Spreadsheet Format
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Slide 9
Incoming Electronic Data
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Open in
SAS
Electronic NDA
SAS Transport
Open in
SAS Viewer
Desktop
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Import in JMP
Stat/Transfer
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Access/Excel
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Other
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Slide 10
NEDAT Objectives
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Slide 11
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NDA Electronic Data Analysis
Training (NEDAT)
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Lesson 2 - Accessing
Electronic Data
Electronic data, currently in SAS Transport file format, submitted to CDERs 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, Microsofts Internet Explorer, Adobe Acrobat, and The SAS
System Viewer are used to complete the tasks in this chapter.
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
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.
11
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
Definition
12
Link to SAS
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.
!
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
13
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
Print Datasets
Sort by column
14
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
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.
15
Pulldown
Menu
Toolbar
Row
Numbers
Column
Headings
Main View
Window
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:
!
The variable names now appear in the column header. Set this Label view to your preference.
Result
or keys
or keys
[CTRL] + or [CTRL] +
[CTRL] + or [CTRL] +
16
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.
Nonconsecutive
Selected Row
Series
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:
!
17
Sort
Descending
Selected
Column
Sort
Ascending
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.
18
Variable
Query
Results
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.
Enter the text you wish to find. Look for patient 0290029043
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.
19
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.
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.
20
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.
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
21
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:
!
Move your pointer onto the desktop and right-click. A pulldown menu will appear.
22
File
File
Copy
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.
23
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 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?
How much available hard drive space is recommended for optimum PC performance?
25
About StatTransfer
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
Quattro Pro
Epi Info
SAS Datasets
Excel
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 formats 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:
!
Dialog Box
Tabs
Transfer
Button
Input File
Type
Output File
Type
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:
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
29
Use the pulldown arrow in the Input File Type: field to choose the SAS
Transport File option
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
SAS XPT
Input
Excel Output
Transfer
Button
30
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)
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
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.
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:
!
Toolbars
Formula Bar
Column
Letters
Row
Numbers
Variables
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
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
31
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
Formula Calculations
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:
!
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
32
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
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.
33
Click the Reset Button at the bottom of the Stat Transfer window
Make sure to choose Access 95-97 in the Output File Type field
XPT Input
Repeat the previous conversion steps, this time converting the file
Z:\N123456\CRT\DATASETS\09\DEMOG.xpt
MS Access
Output
After converting the second table, click the Exit button on StatTransfer.
34
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
Make sure the Open an Existing Database radio button is checked and choose the
More Files option
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.
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
35
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:
36
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
Click on the Lab value vs race query that has been created
DEMOG_JM
variables
Lab1_JMP
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.
!
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
37
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:
In the Open window of StatTransfer, what field do I need to change to open a SAS
Transport file?
What is a Variable?
Can I open the SAS Transport files located on the network to perform my analysis?
NDA Electronic Data Analysis Training Lesson 3: Conversion and Analysis Tools
39
Launch JMP
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:
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:
!
You may also wish to side step this procedure in the future by creating a desktop shortcut to
JMP.
To create a desktop shortcut:
!
42
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)
Either one of these option swill launch JMP and take you to the main JMP screen.
Pulldown
Menu
Toolbar
Rows
Columns
43
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 Open
Cursor
Forms
Scroll Bars
44
Result
or keys
or keys
[CTRL] + or [CTRL] +
[CTRL] + or [CTRL] +
[Home] or [End]
Cursor Forms
Cursor forms are present and can be selected to do the following functions:
- the default cursor form, present when you hover over the deselect areas in the
arrow
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
data cell
- this is a vertical blinking bar which allows you to edit text in a column header or
- is present when you move into a column or row selection area. Use the open
open cross
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
45
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
Nonconsecutive
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.
Highlight PTID
46
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:
!
Those columns now disappear from the table. To view the columns again:
!
Click OK
47
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:
!
Data Type
Notes
Modeling
Type
Content
Col Name
Validation
Data Type
Modeling Type
Data Source
Notes
Variable label
48
49
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.
To test your knowledge of the concepts and techniques you learned in this lesson, answer the
following questions:
Can JMP view the SAS Transport NDA data files located on the network?
51
Subset Command
Search Command
Group Summary
Distribution of Y
Exclude/Include
Fit Y by X
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:
!
Click Add
Variables
Ascending/D
escending
Sort By:
variables
54
Click OK
Variables
Free form
Characters
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.
!
Subset
Variable
Only those highlighted serum sodium rows and columns appear in the new table.
55
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.
!
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.
!
56
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.
!
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.
!
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).
!
57
Select LVALUE
Select PHASE
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:
!
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
58
3. Select the original table and subset the data to get a table for just serum sodium values.
!
Go to Window | LAB1_JMP
Click on the right square above the variable name LVALUE in the column header
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
NDA Electronic Data Analysis Training Lesson 5: JMP Tools
59
Click OK
LVALUE
rows
3. Distribute by Y
!
60
With Baseline
Without Baseline
The chart now excludes the baseline values from the analysis.
In the Data Source: field select Formula from the drop down selection box
61
Column
Selector List
Formula
Display Area
Keypad
, in the Keypad
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
62
Click OK
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
!
63
Column
Select
X/Y Buttons
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:
!
Click X button
Click OK
Analysis
Options
64
P value
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.
Place your cursor over the first cell in the table. Make sure open cross,
(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.
Selected
Row/Columns
, is displayed
Selection
Box
65
Place the cursor at the open end of the scissors on any corner on the chart
Selection
Box
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:
!
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.)
66
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.
!
Make sure the Scissors tool is selected. Click and drag a box over the Analysis of Variance
table
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!
67
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.
To test your knowledge of the concepts and techniques you learned in this lesson, answer the
following questions:
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?
69
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:
Additional Training
Help Menu
OIT Support
Peer Support
71
Double-click on My Computer
Hold [CTRL] down and click on both the nedat.pdf and the 2353dft.pdf files. Both files
should be highlighted.
Once the files are done being copied, remove the floppy disk
72
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.
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
SECTION 27
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
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:
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.
Chapter 1 NEST
Presentation
Please use the blank lines to take notes during the presentation.
Slide 1
_______________________________
_______________________________
_______________________________
CDER/OIT Training
Please Sign-In Before Seating
and Make Sure to Logon with
Your Username
_______________________________
_______________________________
_______________________________
_______________________________
____________________________
Slide 2
NEST Overview
_______________________________
_______________________________
_______________________________
_______________________________
Blueprint of Guidance
_______________________________
NEST Objectives
_______________________________
_______________________________
____________________________
_______________________________
Slide 3
CDERs 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
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
Accessed by Reviewers
_______________________________
_______________________________
____________________________
Slide 5
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
____________________________
Slide 6
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
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Slide 7
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
____________________________
Slide 8
_______________________________
_______________________________
Document Information
Links:
Title Field
TOCs link to
contains pertinent
corresponding
information to each
PDFs
file (patient ID#,
Bookmarks
Site #, Study #,
created as TOCs
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
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
_______________________________
____________________________
Chapter 2 - Accessing
Electronic Submissions
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 reviewers 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 Microsofts Internet Explorer are used to complete the
tasks in this chapter.
In the NDA Quick Search field enter the NDA number and press the Search button
Quick Search
Field
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.
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.
Lift your finger off of the mouse. A pulldown menu will appear.
10
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
Choose Properties on the pulldown menu. Note the free disk space on the C: drive and
click OK.
11
Free Disk
Space
Used Space
Free Space
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.
NDA Electronic Submission Training Chapter 2: Accessing electronic submissions
12
Move your pointer onto the desktop and right-click. A pulldown menu will appear.
Folder Copy
Exercise 2-5: Check the size of the N123456\CMC folder and copy it to your
desktop. Close all open windows when complete.
13
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 find the location of and NDA or Review using the EDR?
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?
15
Chapter 3 - Exploring
Electronic Submissions
In this chapter, you will learn the following:
17
Access the NDA via the EDR or map to the NDA shared area
Command
Bar
Palette Menu
Document
Pane Menu
Tool Bar
Document
Pane
Navigation
Pane
Status Bar
18
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.
19
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).
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.
20
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.
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.
21
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,
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:
Move your pointer over a bookmark in the navigation pane and click to go that selection
22
Navigation
Pane
Bookmarks
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.
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
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.
23
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.
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.
).
To add indexes:
Clicking on them
24
Available
Indexes
Click OK
Add Button
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
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
NDA Electronic Submission Training Chapter 3: Exploring electronic submissions
25
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:
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.
26
Folder
Table of Contents
Document Information
Field
NA
Information
NA
Labeling
Title
brand name
Subject
generic name
Author
Keywords
Summary
NA
CMC
Title
drug substance files
Environmental assessment
Title
Summary document
Title
Study Subfolders
27
Folder
Clinical Microbiology
Document Information
Field
Title
Information
summary document
Studies
Clinical
Title
study reports
Safety Update
NA
Statistical Section
Title
Study reports
Case Report Tabulations (CRTs)
Title
Title
28
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.
29
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.
30
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
following questions:
What is the difference between the Find tool and the Search command?
31
Summarize Annotations
Copy and Paste Graphics using the ISI Graph Copy Plus lug-in
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.
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
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:
Holding down on the mouse, drag to the right to select the Text Annotations tool,
34
Text
Annotation
Click where you want to place the text annotation, or drag a rectangle to create a text field
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.
, in the toolbar
, when finished
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
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Note
Window
Doubleheaded arrow
, 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:
36
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:
Right-click on the closed noted, then choose the desired option from the menu
or
37
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:
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:
At the bottom of the Navigation Pane, click on the Start Annotation Scan,
, button
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Annotation
Scan
Hyperlinks
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.
Click OK
39
Make sure the type is Text-Flow (If not, right-click in the paragraph and choose Text |
Flow from the popup menu)
On that applications 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.
40
Make sure the type is Table (If not, right-click in the table choose Table from the popup
menu)
On that applications 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.
41
On the tool bar, select the ISI Graph Copy Plus button,
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.
On that applications pulldown menu, go to Edit | Paste or click the paste button on the
toolbar
42
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:
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.
43
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
following questions:
Can you save notes on the network copies of the electronic submissions files?
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?
45
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:
Acrobat Preferences
OIT Support
Peer Support
47
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.
NDA Electronic Submission Training Chapter 5: Support
48
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.
49
51
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.
Exercise 2-3: Map the drive letter Z: to sample NDA 123456 and DO NOT
reconnect at logon.
Select Z as the Drive letter and enter \\cds006\samplenda in the path field
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
Lift your finger off of the mouse. A pulldown menu will appear.
52
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 2-5: Check the size of the N123456\CMC folder and copy it to your
desktop.
To check the size of the folder:
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
Move your pointer onto the desktop and right-click. A pulldown menu will appear.
Exercise 3-1: Open the table of contents for NDA 123456 and go to the labeling
table of contents.
53
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 destinationthe 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
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
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.
54
You can also use the magnification option on the status bar,
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 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.
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.
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.
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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
Remove any existing indexes by clicking on them, then clicking on the Remove button
Click OK
You will receive the message No documents were found that matched your query.
Click OK
Put a comma (,) after 0000 (you can also use the Boolean expression OR instead of the
comma)
56
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:
Save the summary document to the C:\Classes\NEST folder (The network copy is readonly)
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,
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
Move your pointer on the line around the third paragraph so the arrow, ", appears and
double-click
Type in your note and click the minus bar to close the note field
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
Type in your note and click the minus bar to close the note field
57
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:
Annotation Palette:
At the bottom of the Navigation Pane, click on the Start Annotation Scan 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.
Click OK
58
Make sure the type is Text-Flow (If not, right-click in the paragraph and choose Text |
Flow from the popup menu)
, 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.
Make sure the type is Table (If not, right-click in the table choose Table from the popup
menu)
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.
On the Tool Bar, select the ISI Graph Copy Plus button,
59
When you let go of the mouse, wait a few moments until the box disappears
Go to Microsoft Word
Click OK
Exercise 5-1: Look up information about page layouts in the Acrobat Guide.
Use the index to search for Page layouts. Click the last page button,
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
Click on the for document viewing 41-43 link at the top left of the page. Browse
through the topic
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