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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
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Background for eCTD Applications
e-CTD is an interface for Industry to Agency
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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
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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
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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
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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
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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
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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)
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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.
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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)
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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.
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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
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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
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File Structure, Module 2 - Summaries
m2m2--summariessummaries
2222--introintro
2323--qosqos
2424--nonclinnonclin--overover
2525--clinclin--overover
2626--nonclinnonclin--sumsum
2727--clinclin--sumsum
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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
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Actual Submission
--
CTDCTD--123456123456
00000000
m1m1
m2m2
m3m3
m4m4
m5m5
utilutil
00010001
00020002
Original Main Submission FolderOriginal Main Submission Folder
Rev. etc.Rev. etc.
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2222--introintro
2323--qosqos
2424--nonclinnonclin--overover
2525--clinclin--overover
2727--clinclin--sumsum
2626--nonclinnonclin--sumsum
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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
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Directories used to create Template: File Organization
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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
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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
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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
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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
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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
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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
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Process - Overview
Authoring
Review
Publishing
Compilation
Submit
SpONSOR
Validate
Load/ Archive
Review
SpONSOR
AGENCY
QA
GATKEEPER
eCTDViewer
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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
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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
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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)
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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
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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
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Publishing of eCTD
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Thank You
Nandkumar Chodankar (Ph D Tech)
Acknowledgements
• Dr. Vinay Naik
• Mr. Babu K Suri
• Mamta Wani
Acknowledgements
• Dr. Vinay Naik
• Mr. Babu K Suri
• Mamta Wani