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1/13/2010 1 e-CTD norms for INDs, DMFs & CTA study Nandkumar Chodankar (Ph D Tech) IPA/EDQM/IPC Technical Conference Jan. 28 & 29th 2010; Hyatt Regency, Mumbai India IPA/EDQM/IPC Technical Conference Jan. 28 & 29th 2010; Hyatt Regency, Mumbai India This presentation includes Jan. 29th 2010 Nandkumar Chodankar Ph D Tech 2/46 Topic Pages 1 Background (CTD 5 Modules) & General Information 3-6 2 Advantages of eCTD and eCTD Backbone; XML 7-12 3 eCTD Contents e.g., Module 1 & 2 Folders 13-23 4 How to Simplify eCTD Submission for the Reviewer 24-25 5 Process of Implementation/Process Flow 26-27 6 Authoring, Publishing and Technology 28-36 7 Success Formula & Ten Commandments 37-41 8 Summary and Next Step 42- 47

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1/13/2010

1

e-CTD norms for INDs, DMFs & CTA study

Nandkumar Chodankar (Ph D Tech)

IPA/EDQM/IPCTechnical Conference

Jan. 28 & 29th 2010; Hyatt Regency, Mumbai India

IPA/EDQM/IPCTechnical Conference

Jan. 28 & 29th 2010; Hyatt Regency, Mumbai India

This presentation includes

Jan. 29th 2010 Nandkumar Chodankar Ph D Tech 2/46

Topic Pages

1 Background (CTD 5 Modules) & General Information

3-6

2 Advantages of eCTD and eCTD Backbone; XML

7-12

3 eCTD Contents – e.g., Module 1 & 2 Folders 13-23

4 How to Simplify eCTD Submission for theReviewer

24-25

5 Process of Implementation/Process Flow 26-27

6 Authoring, Publishing and Technology 28-36

7 Success Formula & Ten Commandments 37-41

8 Summary and Next Step 42- 47

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Module 1Regional

Administrative Information

Module 2 QualityOverall

Summary

Module 1 is Not Part of CTD

This is Regional Requirement

NDSNDA

NonclinicalOverview

ClinicalOverview

ClinicalSummary

NonclinicalSummary

Module 3

Quality

Module 4

NonclinicalStudy Reports

Module 5

ClinicalStudy Reports

CTD

Module 2

Jan. 29th 2010 3/46Nandkumar Chodankar Ph D Tech

Background for eCTD Applications

e-CTD is an interface for Industry to Agency

Jan. 29th 2010 4/46Nandkumar Chodankar Ph D Tech

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eCTD norms for INDs, DMFs & CTA (Clinical Trial Appl.) Study

Guidance for providing Regulatory Submission in Electronic format - Human Pharmaceutical Product applications and related submissions using the eCTD Specifications (June 2008- Rev.2)

ICH M2 EWG provides specifications like

– Document Type Definitions (DTD),

– Change Management,

– Procedure and

– Specification on Modules

Jan. 29th 2010 5/46Nandkumar Chodankar Ph D Tech

General InformationeCTD is preferred standard for submission to

the Regulatory Authorities (Paper is still accepted but not preferred, one needs to ask for a waiver for paper submission)

One can convert CTD to eCTD at any time, permission is not required

Once eCTD, always eCTD

Jan. 29th 2010 6/46Nandkumar Chodankar Ph D Tech

Goal of the Authorities is to Implement a standard -based end-to-end fully electronic receipt, review, and dissemination environment)

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eCTD -Advantages to the Reviewer:-Builds overall Efficiency

An understanding of the reviewer’s requirement is essential, so that

The Reviewer finds it easy to review

The tool used should

Facilitate to locate the documents

Has capabilities to Search & Sort

Map Checklist to CTD

Has standardized, consistent headings

Based on the size of the Organization one needs to build in-house capability &/or seek advice from Agency/experts

Jan. 29th 2010 7/46Nandkumar Chodankar Ph D Tech

Advantages of eCTD

• Capability for Viewing and Printing of documents, using simple browser

• Capability for Annotation of documentation

• Exporting of document to databases

• Searching within and across applications

• Navigation throughout the eCTD and its subsequent amendments and/or variations

• Through the use of XML as a means of carrying & transmitting the data to the recipient

• Capability to Copy and Paste

Jan. 29th 2010 8/46Nandkumar Chodankar Ph D Tech

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The eCTD “Backbone”

The eCTD is designed around the concept of a backbone – the place to start

The backbone is similar to a Folder/Box File or container that holds the files that are part of the submission.

The backbone is based on an XML

Document Type Definition (DTD)

The DTD describes the hierarchical structure according to the CTD

The eCTD is designed around the concept of a backbone – the place to start

The backbone is similar to a Folder/Box File or container that holds the files that are part of the submission.

The backbone is based on an XML

Document Type Definition (DTD)

The DTD describes the hierarchical structure according to the CTD

Jan. 29th 2010 9/46Nandkumar Chodankar Ph D Tech

Spin

eSpine/Backbone

What is XML• XML stands for EXtensible Markup Language

• This is much like HTML

• XML was designed to carry data, not to display data

– It does not DO anything by itself.

– It was created to structure, store, and transport information.

• The tags of XML are not predefined. One must define one’s own tags (Use freedom but with logic)

• XML is designed to be self-descriptive

• It is recommended by the World Wide Web Consortium(W3C)

Jan. 29th 2010 10/46Nandkumar Chodankar Ph D Tech

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The Purpose of the XML backbone

To manage meta-data, for the entire submission:

Information about submitting and receiving organization

Manufacturer, publisher, ID

Kind of the submission, and related data items &

For each document within the submission:

Versioning information, language,

Descriptive information such as document names and checksums.

To constitute a comprehensive table of contents and provide corresponding navigation aids.

Jan. 29th 2010 11/46Nandkumar Chodankar Ph D Tech

What does eCTD include?

The eCTD submission is composed of:

Directory structure

XML “eCTD instance”

Content files

The directory structure is composed of directories and files

Name of the files and directories are the identifiers

(Recommended file names are illustrated)

Jan. 29th 2010 12/46Nandkumar Chodankar Ph D Tech

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Module 1’s Purpose is to:-

Archive regional documents

Application management

Status

Business

Special regulatory programs

Provides the legal and regulatory framework for the application/submission

Module 1 sets the regulatory and legal framework

for applications. This also helps in correlating the

subsequent submissions / information under

appropriate heading.

Jan. 29th 2010 13/46Nandkumar Chodankar Ph D Tech

CFR Citation eCTD/STF Heading

NUMBER TITLE MODULE NUMBER TITLE

312.7(d) Charging for and

commercialization

of investigational

drugs

1 1.12.2 Request to

Charge

312.10 Waivers 1 1.12.5 Request for a

waiver

312.23

(a)(1)

Cover sheet (Form

FDA 1571)

1 1.1.1 Application

form: FDA form

1571

312.23(a)(2) Table of Contents N/A N/A N/A

314.50(h) Patent Information 1 1.3.5.1 Patent

Information

TOC Mapping- US Submission

Jan. 29th 2010 14/46Nandkumar Chodankar Ph D Tech

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Module Folder Names: m1, m2, m3, m4, m5.

Pre-Set Folder/File Names

Section in CTD (Module 2) Section in eCTD

Description Folder Name

2.2 Introduction 22 -intro

2.3 Quality overall summary 23 -qos

2.4 Nonclinical Overview 24 -nonclin-ove

2.5 Clinical Overview 25 -clin-over

2.6 Nonclinical Written and Tabulated Summaries

26 -nonclin-sum

2.7 Clinical summary 27 -clin-sum

Your File Name (e.g., for CTA ) eCTD Version

Study Report 1 study-report-1.pdf

Study Report 2 study-report-2.pdf

Study Report n study-report-n.pdf

Jan. 29th 2010 15/46Nandkumar Chodankar Ph D Tech

File Structure, Module 2 - Summaries

m2m2--summariessummaries

2222--introintro

2323--qosqos

2424--nonclinnonclin--overover

2525--clinclin--overover

2626--nonclinnonclin--sumsum

2727--clinclin--sumsum

Jan. 29th 2010 16/46Nandkumar Chodankar Ph D Tech

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• Include a Table of content for documents that are more than a few pages

Include hyperlinks where text refers to other document or other information, because Review becomes difficult without hyperlinks

– Appropriate hyperlinks makes review efficient

– One instance per page is acceptable

Elements for reviewable ANDA

For eCTD it is essential to have links “to” & “from” Module 2 and Module 5 because reviewers appreciate a singledocument with links to bioequivalence

Jan. 29th 2010 17/46Nandkumar Chodankar Ph D Tech

Actual Submission

--

CTDCTD--123456123456

00000000

m1m1

m2m2

m3m3

m4m4

m5m5

utilutil

00010001

00020002

Original Main Submission FolderOriginal Main Submission Folder

Rev. etc.Rev. etc.

Jan. 29th 2010

2222--introintro

2323--qosqos

2424--nonclinnonclin--overover

2525--clinclin--overover

2727--clinclin--sumsum

2626--nonclinnonclin--sumsum

18/46Nandkumar Chodankar Ph D Tech

32323232

33333333

34343434

35353535

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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.

Next slide defines the directories used to create this template

Jan. 29th 2010 19/46Nandkumar Chodankar Ph D Tech

Directories used to create Template: File Organization

Jan. 29th 2010 20/46Nandkumar Chodankar Ph D Tech

Number CTD section number

Title CTD Title

Sequential

Number

(1 – 378)

Element Element name in the Backbone

File/Directory Relative path of the File/Directory

Comment Comments

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Example

Number 2.3

Title Quality Overall Summary

Sequential

Number

(1 – 378)

Element m2-3-quality-overall-summary

File/Directory m2/m23-qos

Comment Refer to the Granularity Annex of the

M4 Organization Document

Jan. 29th 2010 21/46Nandkumar Chodankar Ph D Tech

The Specification’s Requirements Only Specific File Formats are Allowed:

PDF, SAS EXPORT, ASCII, XML

PDF files should preferably be no larger than 100 megabytes.

PDF Files should have hyperlinked TOC

Pages should be properly oriented.

Page orientation of landscape pages should be set to landscape prior to saving the PDF document in final form

Scanning should be avoided (because of large megabytes)

Hypertext links can be designated by

Using “Rectangles”

Or by using “text” in “blue color”

The subject matter is specifically associated with the lowest heading in the table of contents hierarchy

Jan. 29th 2010 22/46Nandkumar Chodankar Ph D Tech

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Permitted File Formats

text/css css

text/html html or htm

text/xml xml

text/xml xml

application/pdf pdf

application/rtf rtf

application/vnd.ms-excel xls

image/jpeg jpg

image/png png

image/gif gif

DTD dtd

XPT (SAS) xpt

XSL xsl

Jan. 29th 2010 23/46Nandkumar Chodankar Ph D Tech

By using the correct Regional XML File, e.g., “us regional.xml”

Using the correct regional checksums for DTD, etc., if published

Ensuring that all files that are referenced by “xlink:href” actually exist

Ensuring there are no unreferenced files in folders “m1” through “m5”

Using folder & file names given in the Specification If not, ensure they follow correct naming

conventionsNot using Node ExtensionsEnsuring that the lowest level heading elements

contain at least one leaf.

How one can simplify eCTDsubmission for the Reviewer

Jan. 29th 2010 24/46Nandkumar Chodankar Ph D Tech

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Specific File LocationsSubmission Folder Files

ctd-123456/0000 index.xml

index-md5.txt

ctd-123456/0000/m1/us us-regional.xml

ctd-123456/0000/m2

ctd-123456/000/m3, /m4, /m5

m2/22-intro…

m2/23-qos…

m2/24-nonclin-over…

m2/25-clin-over/ clinical-overview.pdf

m2/26-nonclin-sum…

m2/27-clin-sum…

As in Appendix 4

ctd-123456/0000/util ich-ectd-3-2.dtd

us-regional-1-0.dtd

Jan. 29th 2010 25/46Nandkumar Chodankar Ph D Tech

Process and Implementation If the “Publishing Process” for eCTD is in place, most of

the time it will remain unchanged.

Areas one should pay more attention to are:

– Authoring

– Workflow

– Organization of Documents

– Technology used

eCTD is the last step

Jan. 29th 2010 26/46Nandkumar Chodankar Ph D Tech

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Process - Overview

Authoring

Review

Publishing

Compilation

Submit

SpONSOR

Validate

Load/ Archive

Review

SpONSOR

AGENCY

QA

GATKEEPER

eCTDViewer

Jan. 29th 2010 27/46Nandkumar Chodankar Ph D Tech

Authoring: Key to Successful eCTD

Granularity is “The Most Important Part”

Importance of thorough understanding of CTD sections &

Management of Multiples: – Drug Product

– Drug Substance

– Manufacturers

– Indication

– Excipients

– Literature references

Jan. 29th 2010 28/46Nandkumar Chodankar Ph D Tech

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Authoring Granularity Impact

Study Reports/M3 - when relevant information

is changed at any point in the product's lifecycle, replacements of complete documents/files

should be provided if originally submitted as a single file

Consider standardizing naming conventions using centrally managed system

Applicant Name, Product, Substance, Manufacturer, Excipient, Indication, etc

Folders and files along with a standard folder structure

A realistic & usable standard (defined by applicant) for cros linking:

Internal linking

External linking

Jan. 29th 2010 29/46Nandkumar Chodankar Ph D Tech

Authoring – Recommendation

Standardized templates should be used

for authoring all types of documents

Should be “formatted” according to ICH CTD or E3 standards depending on the type of the document

Fonts, styles and formatting according to ICH and regional requirements

Stored centrally with restricted access to authorized individuals according to their role

TOC (Table of Contents), List of Figures, Tables and Graphs, and List of Appendices created using standard MS Word functionality (or similar)

Jan. 29th 2010 30/46Nandkumar Chodankar Ph D Tech

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Publishing of eCTD

eCTD is not a critical step in the e-Submission process, PDF publishing is most critical

It does not change PDF Publishing requirements

Navigational features in the PDF are very important

Bookmarks

Hypertext Links

Jan. 29th 2010 31/46Nandkumar Chodankar Ph D Tech

Ease of Navigability

Document Table of Contents

Bookmarking & Hypertext Linking

Open to Bookmark and Page view

Verify bookmarks/links that takes the Reviewer to correct location/destination

Verify magnification: Inherit zoom

Common Bookmarks (one click approach) Include bookmarks back to higher levels within Document group/section

Jan. 29th 2010

Publishing of eCTD

32/46Nandkumar Chodankar Ph D Tech

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Publishing - Bookmarks

Create bookmarks which match the TOC

Match TOC hierarchy up to 4 levels

Names should be intuitive;

Protocol instead of Appendix 1

List of Investigators instead of Appendix 2

Open view hierarchy - Expand to three levels

QC: spelling errors and completeness

When TOC is not present, create bookmarks to sections and sub sections

Jan. 29th 2010 33/46Nandkumar Chodankar Ph D Tech

Publishing - Hypertext Linking

All TOC items, including: Table, Figures, Listings and References

Attributes, if Electronic source: blue text with invisible rectangle

Scanned source: black text with visible thin, blue rectangle

Internal Supporting annotations, related sections, references, appendices, table & figures

(not located on the same page as narrative text)

Functionality: relative vs. absolute path

Jan. 29th 2010 34/46Nandkumar Chodankar Ph D Tech

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Technology

Capabilities and solutions should be based on the requirements or need Small scale investment (SMB) Standards and Procedures

Adobe Acrobat (use v7 or the latest version)

Acrobat Plug-ins

eCTD Tools/Application

Scanner

Large scale investment Document Management System

Enterprise level Publishing System

Maintenance and Support

Jan. 29th 2010 35/46Nandkumar Chodankar Ph D Tech

Technology

Pay attention to details,

Essentials of the solution should offer:

Easy-to-use user interface

Templates

Built-in intelligence to create or modify XML

Ability to create/validate the XML and Directory structure

Multi-region and language support

Ability to maintain submission integrity

Reduced anxieties

Jan. 29th 2010 36/46Nandkumar Chodankar Ph D Tech

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Success Formula

Send in eCTD format (with XML backbone)

Complete a sample of eCTD if you have never submitted eCTD before

Read and Adhere to the published guidance and specification documents

Refer to the Elements of Review - NDA

Communicate with FDA when you have questions ([email protected])

• Initiate contact prior to assembling application

• Arrange participation in eCTD Pilot

Jan. 29th 2010 37/46Nandkumar Chodankar Ph D Tech

Sample of eCTD Process

Successful sample is reviewable submission Prepare a sample that closely matches your real document

submission Include Module 1, 2, 3 and 5, SPL, hyperlinks In Practice no reviewer will review your sample submission,

the info will be stored separately from real submissions The sample processing takes less than 30 days from the

time of receipt Clarify any guidance or other questions in advance Obtain professional services or tools. Refer instructions at

http://www.fda/cder/regulatory/ersr/ectd.htm

Jan. 29th 2010 38/46Nandkumar Chodankar Ph D Tech

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Success Formula Continued

• Clarify Guidance questions

• Contact addresses: [email protected]

• CDER: ODEI - ODEV

– ALL electronic submissions for original applications, supplements, and amendments, must be sent to the Central Document Room

• CDER: ODEVI

– All electronic submission to the ODEVI document room

• CDER: OGD

– All electronic submission to the OGD document room

• Send only ONE copy of the electronic submission

• Use the correct electronic media and choose appropriate type according to the size of submission

• Place the electronic media in the first volume

Jan. 29th 2010 39/46Nandkumar Chodankar Ph D Tech

Success Formula Continued• Remember that eCTD submission

– Should not include any paper if Part 11 compliant electronic signatures are available (otherwise include paper documents requiring original signatures)

– Should include all required eCTD files

– Should include all required forms, letters, and certifications

– Be sure ALL files submitted are referenced in XML backbone

– Do not use Node extensions

Jan. 29th 2010 40/46Nandkumar Chodankar Ph D Tech

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Ten Commandments for success

1. Files Referenced are in the XML Backbone

2. eCTD Submissions include Module 1

3. Application’s Numbers is 6 Digits

4. Sequence Numbers are 4 Digits

5. Remove Node Extensions

6. MD5 Checksum are Correct7. Documents Confirm to eCTD Granularity8. XML used is with Standard Components9. PDF Hyperlinks/Bookmarks are Correct10. PDF Documents include TOCs

Jan. 29th 2010 41/46Nandkumar Chodankar Ph D Tech

Make sure that:

SummaryeCTD should be viewed as an advantage

Future Change is inevitable

Life Cycle management has lot of advantages

Technology is bound to improve

On-going process requires fine tuning

Knowledge is important, early involvement will yield a better ROI over time

XML is only a very small piece of the puzzle, focus should be on the document contents

One should familiarize with eCTD and regional guidance and specifications

Jan. 29th 2010 42/46Nandkumar Chodankar Ph D Tech

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Summary – Way forward

Management Team should Create a task force/special project

Education/Training for all contributors

Regulatory Make sure the documents delivered are granular

Publish or ready to Publish

Clinical/Nonclinical ICH E3 CSR

CDISC standards for Data

Granularity

Jan. 29th 2010 43/46Nandkumar Chodankar Ph D Tech

Summary – Way Forward Cont…

CMC Granularity Product, substance, manufacturer and excipient level

metadata and grouping

Authors Use CTD compliant templates Consider ICH and regional standards and

requirements before creating documents Focus on creating documents that could be reusable

across regions

Jan. 29th 2010 44/46Nandkumar Chodankar Ph D Tech

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Summary – Way forward Cont…

Reviewer (QA/QC) Understand ICH and regional specifications and

guidelines Content Technical

IS/IT Make sure you have enough resources to support

new (XML) technical requirements Storage and access Training

Jan. 29th 2010 45/46Nandkumar Chodankar Ph D Tech

Thank You

Nandkumar Chodankar (Ph D Tech)

[email protected]

Acknowledgements

• Dr. Vinay Naik

• Mr. Babu K Suri

• Mamta Wani

Acknowledgements

• Dr. Vinay Naik

• Mr. Babu K Suri

• Mamta Wani