eCTDeCTD18.11.201018.11.2010

E.Rama KrishnaE.Rama KrishnaDGMDGM--Regulatory AffairsRegulatory Affairs

Medreich LimitedMedreich Limitedramakrishna.e@medreich.comramakrishna.e@medreich.com

eCTDeCTD18.11.201018.11.2010

E.Rama KrishnaE.Rama KrishnaDGMDGM--Regulatory AffairsRegulatory Affairs

Medreich LimitedMedreich Limitedramakrishna.e@medreich.comramakrishna.e@medreich.com

Outline of Presentation

• eCTD

• eCTD Benefits

• How it is different to Paper/Document CTD

• eCTD submission goals

• eCTD Implementation

• Regulatory Contact Information

• Initial Considerations

• eCTD – Modules

• eCTD Management Softwares

• Don’ts

• Points to be considered

• eCTD

• eCTD Benefits

• How it is different to Paper/Document CTD

• eCTD submission goals

• eCTD Implementation

• Regulatory Contact Information

• Initial Considerations

• eCTD – Modules

• eCTD Management Softwares

• Don’ts

• Points to be considered

eCTD• eCTD – electronic Common Technical Document

• The eCTD is the electronic equivalent to the CTD.

• Regulatory Perspective

• “The eCTD is defined as an interface for industry toagency transfer of regulatory information while atthe same time taking into consideration thefacilitation of the creation, review, lifecyclemanagement and archival of the electronicsubmission.”

• Common structure for Modules 2 through 5

• Agency specific requirements for Modules 1

• eCTD – electronic Common Technical Document

• The eCTD is the electronic equivalent to the CTD.

• Regulatory Perspective

• “The eCTD is defined as an interface for industry toagency transfer of regulatory information while atthe same time taking into consideration thefacilitation of the creation, review, lifecyclemanagement and archival of the electronicsubmission.”

• Common structure for Modules 2 through 5

• Agency specific requirements for Modules 1

eCTD• Technical Perspective

• Structured set of common folders structure forcontaining PDFs and SAS files on a CD/DVD (Canalso be submitted through Agency web portals)

• The eCTD backbone is an XML file representing thestructure of the submission, it includes links to filesand other metadata such as check sum information.The schema for the XML is very rigid.

• PDF hyperlinks

• Study Tagging Files (XML)

• Technical Perspective

• Structured set of common folders structure forcontaining PDFs and SAS files on a CD/DVD (Canalso be submitted through Agency web portals)

• The eCTD backbone is an XML file representing thestructure of the submission, it includes links to filesand other metadata such as check sum information.The schema for the XML is very rigid.

• PDF hyperlinks

• Study Tagging Files (XML)

eCTD• More efficient use of resources, expedites submissions,

less cost and stress to the organization

• Granularity of files submitted is small (there are nolonger issues of creating large volumes of PDFs).

• Increased potential for reusing the same submissioncontent across agency submissions.

• The standard, and many of the modules have beenagreed upon by the main worldwide agencies.

• More efficient use of resources, expedites submissions,less cost and stress to the organization

• Granularity of files submitted is small (there are nolonger issues of creating large volumes of PDFs).

• Increased potential for reusing the same submissioncontent across agency submissions.

• The standard, and many of the modules have beenagreed upon by the main worldwide agencies.

eCTD• The new standard accounts for amendments to

submissions (i.e.lifecycle)–so only what has changedneeds to be re-submitted (hitherto, everything had to bere-submitted).

• This lifecycle information is represented in the XMLschema

• Once a submission is sent in eCTD format all futuresubmissions for the application should be in eCTDformat.

• Opportunity to use Part 11 Compliant ElectronicSignatures

• Use only file formats specified in the guidance

• The new standard accounts for amendments tosubmissions (i.e.lifecycle)–so only what has changedneeds to be re-submitted (hitherto, everything had to bere-submitted).

• This lifecycle information is represented in the XMLschema

• Once a submission is sent in eCTD format all futuresubmissions for the application should be in eCTDformat.

• Opportunity to use Part 11 Compliant ElectronicSignatures

• Use only file formats specified in the guidance

eCTD Benefits• Easy to distribute and review

• Highly organized electronic table of contents

• Searchable

• Self-validating

• Integrated document and life-cycle management

• Cross submission integration

• Living document

• New, replace, append & delete

• Easy to distribute and review

• Highly organized electronic table of contents

• Searchable

• Self-validating

• Integrated document and life-cycle management

• Cross submission integration

• Living document

• New, replace, append & delete

How it is different to Paper/Document CTD

• Overall Table of contents provided in XML

• Utility files to enable technical conformance andviewing

• Submission Folders, XML and Utility Files are createdautomatically if an eCTD builder is used.

• Generally high level of granularity in documents

• Structure is more precise

• Lifecycle Management of the submission is easier.

• Overall Table of contents provided in XML

• Utility files to enable technical conformance andviewing

• Submission Folders, XML and Utility Files are createdautomatically if an eCTD builder is used.

• Generally high level of granularity in documents

• Structure is more precise

• Lifecycle Management of the submission is easier.

eCTD submission goals

• Planning a submission is a major project that requiresskill, experience, teamwork and the involvement ofspecialist IT eCTD vendor software solutions

• Everybody’s in touch using the same rules

• Communication is clear and complete

• Key documents in eCTD are easy to find

• Guidances and specifications are followed

• Planning a submission is a major project that requiresskill, experience, teamwork and the involvement ofspecialist IT eCTD vendor software solutions

• Everybody’s in touch using the same rules

• Communication is clear and complete

• Key documents in eCTD are easy to find

• Guidances and specifications are followed

eCTD submission goals• Providing Regulatory Submissions in Electronic Format

- Human Pharmaceutical Product Applications andRelated Submissions

• Includes NDA, ANDA, BLA, IND, DMF andassociated submissions

• FDA has an inherent desire to work closely withsponsors to provide a submission using the eCTDspecifications and will offer guidance to help smooththe process – Don’t be shy in leveraging their insight.(esub@fda.hhs.gov)

• Utilize a sample submission to ensure that it conformsto the FDA eCTD Guidance (https://esgtest.fda.gov/ui/)

• Providing Regulatory Submissions in Electronic Format- Human Pharmaceutical Product Applications andRelated Submissions

• Includes NDA, ANDA, BLA, IND, DMF andassociated submissions

• FDA has an inherent desire to work closely withsponsors to provide a submission using the eCTDspecifications and will offer guidance to help smooththe process – Don’t be shy in leveraging their insight.(esub@fda.hhs.gov)

• Utilize a sample submission to ensure that it conformsto the FDA eCTD Guidance (https://esgtest.fda.gov/ui/)

eCTD Implementation - FDA

• Jan 1, 2008, eCTD became CDER’s standard forelectronic submission.

• FDA has made it mandatory for all ELECTRONICsubmissions to be in eCTD format since 2007-08.However, paper copies are still accepted. Suitablewaivers will have to be taken before hand.

• The number of ANDA submissions to FDA hasincreased from 72 in the year 2006 to 1550 in 2009

• Jan 1, 2008, eCTD became CDER’s standard forelectronic submission.

• FDA has made it mandatory for all ELECTRONICsubmissions to be in eCTD format since 2007-08.However, paper copies are still accepted. Suitablewaivers will have to be taken before hand.

• The number of ANDA submissions to FDA hasincreased from 72 in the year 2006 to 1550 in 2009

eCTD Implementation - EU(http://esubmission.emea.europa.eu/)

•Requirements on Electronic submissions (Nees and eCTD)and paper documentation for New Application within MRP,DCP or National procedure – Refer CMDh/085/2008/Rev7October 2010)

•From 1st July 2010, the EU M1 v1.4 must be used for alleCTD submissions for all European procedures,

eCTD Implementation - MHRAhttp://www.mhra.gov.uk/Pharmaceuticalindustry/Marketingauthoris

ations/index.htm

•The preferred format for new marketing authorisation (MA)applications is the electronic Common Technical Dossier(eCTD)

•eCTD applications must be created according to the currentspecifications: eCTD specification v 3.2, EU Module 1specification v 1.0, eCTD EU application v 1.0.

•MHRA will accept applications in PDF-only format

•The Summary of Product Characteristics (SmPC) will needto be prepared using the Word template.

•Use the MHRA Adobe Application form which is availablevia the MHRA Portal. This will produce an XML file thatMHRA can upload directly into their database.

•The preferred format for new marketing authorisation (MA)applications is the electronic Common Technical Dossier(eCTD)

•eCTD applications must be created according to the currentspecifications: eCTD specification v 3.2, EU Module 1specification v 1.0, eCTD EU application v 1.0.

•MHRA will accept applications in PDF-only format

•The Summary of Product Characteristics (SmPC) will needto be prepared using the Word template.

•Use the MHRA Adobe Application form which is availablevia the MHRA Portal. This will produce an XML file thatMHRA can upload directly into their database.

Regulatory Contact information

Initial Considerations• Paper CTD versus eSubmission?

• Requirement: if eCTD is submitted, eCTD must bemaintained.

• Creation and long-term management of eCTD requiresIT capability

• Internal resources

• External resources

• Combination

• Paper CTD versus eSubmission?

• Requirement: if eCTD is submitted, eCTD must bemaintained.

• Creation and long-term management of eCTD requiresIT capability

• Internal resources

• External resources

• Combination

Initial Considerations• Approach

• Creation/Construction of original eCTD

• Internal resources: Regulatory and IT

• External resources: eCTD Vendor

• Combination: eCTD build to be done in parallel by ITeCTD Vendor and CRO/Sponsor

• Subsequent eCTD Amendments

• Handle with internal resources

• eCTD validated software purchased/outsourced

• Approach

• Creation/Construction of original eCTD

• Internal resources: Regulatory and IT

• External resources: eCTD Vendor

• Combination: eCTD build to be done in parallel by ITeCTD Vendor and CRO/Sponsor

• Subsequent eCTD Amendments

• Handle with internal resources

• eCTD validated software purchased/outsourced

eCTD Modules• When making an electronic submission, each document

should be provided as a separate file.

• The documents, whether for a marketing application, aninvestigational application, or a related submission,should be organized based on the five modules in theCTD:

• Module 1 includes administrative information andprescribing information,

• Module 2 includes CTD summary documents,

• Module 3 includes information on quality,

• Module 4 includes the nonclinical study reports, and

• Module 5 includes the clinical study reports.

• When making an electronic submission, each documentshould be provided as a separate file.

• The documents, whether for a marketing application, aninvestigational application, or a related submission,should be organized based on the five modules in theCTD:

• Module 1 includes administrative information andprescribing information,

• Module 2 includes CTD summary documents,

• Module 3 includes information on quality,

• Module 4 includes the nonclinical study reports, and

• Module 5 includes the clinical study reports.

eCTD Template

eCTD Screen Shot

eCTD Screen Shot of Module 2

eCTD Screen Shot of Module 3

eCTD Screen Shot of Module 4

eCTD Screen Shot of Module 5

eCTD Screen Shot of Module 5

eCTD Screen Shot of Module 5

eCTD Management Software• eCTDXPress – Image Solutions –http://www

imagesolutions com

• MasterControl Submissions Gateway™ - MasterControl, http://www.mastercontrol.com

• Liquent’s EZsubs® software solution,http://www.liquent.com/

• Data Farm, http://www.datafarminc.com/

• Take solution : www.PharmaReady.com

• Lorenz Life Sciences : www.lorenz.cc

• eCTDXPress – Image Solutions –http://wwwimagesolutions com

• MasterControl Submissions Gateway™ - MasterControl, http://www.mastercontrol.com

• Liquent’s EZsubs® software solution,http://www.liquent.com/

• Data Farm, http://www.datafarminc.com/

• Take solution : www.PharmaReady.com

• Lorenz Life Sciences : www.lorenz.cc

Don’ts• No paper unless required for original signatures

• No Word files or file formats not specified in theguidance

• No electronic submissions or records sent directly to areviewer or project manager

• No electronic desk copies

• No paper unless required for original signatures

• No Word files or file formats not specified in theguidance

• No electronic submissions or records sent directly to areviewer or project manager

• No electronic desk copies

Points to Consider• Include all required eCTD files Define drug substance and product

metadata carefully

• Include all required forms, letters, and certifications.

• Be sure ALL files submitted are referenced in XML backbone

• Do not use Node extensions

• Provide bookmarks with intuitive names

• Useful to have a bookmarks arranged hierarchically

• Provide Hypertext Links

• They enhance navigation tremendously.

• When to provide Hyperlinks?

• Anytime the text refers to a reference (table, figure, etc.) that isnot on the same page. (Validate in the final compilation)

• Include all required eCTD files Define drug substance and productmetadata carefully

• Include all required forms, letters, and certifications.

• Be sure ALL files submitted are referenced in XML backbone

• Do not use Node extensions

• Provide bookmarks with intuitive names

• Useful to have a bookmarks arranged hierarchically

• Provide Hypertext Links

• They enhance navigation tremendously.

• When to provide Hyperlinks?

• Anytime the text refers to a reference (table, figure, etc.) that isnot on the same page. (Validate in the final compilation)

Points to Consider• All literature references must be included

• Define drug substance and product metadata carefully

• Avoid long directory & file path combinations (CDlimit)

• Try to minimize the scanning of documents (OCRconversion)

• Require Microsoft Word, PDF & literature referencesfrom CROs

• Watch out for Adobe Acrobat PDF Creation Bugs fromWord

• Make sure PDFs are the version recommended

• All literature references must be included

• Define drug substance and product metadata carefully

• Avoid long directory & file path combinations (CDlimit)

• Try to minimize the scanning of documents (OCRconversion)

• Require Microsoft Word, PDF & literature referencesfrom CROs

• Watch out for Adobe Acrobat PDF Creation Bugs fromWord

• Make sure PDFs are the version recommended

Points to Consider• Don’t forget to print the md5-index.xml checksum

• Don’t forget the 0 before your IND number

• Your goals is to enhance communication

• Clarity improves reviewability

• Consider application from reviewer’s standpoint

• Create document level Tables of Content withappropriate bookmarks

• Use meaningful file names

• Use clear concise leaf titles

• 100% QA by at least two individuals before submission

• Don’t forget to print the md5-index.xml checksum

• Don’t forget the 0 before your IND number

• Your goals is to enhance communication

• Clarity improves reviewability

• Consider application from reviewer’s standpoint

• Create document level Tables of Content withappropriate bookmarks

• Use meaningful file names

• Use clear concise leaf titles

• 100% QA by at least two individuals before submission

Thank You