Electronic submission requirements for prescription medicines - AU eCTD update

Electronic submission requirements for
prescription medicines
AU eCTD update
Dr John Donohoe
Office of Medicines Authorisation, Market Authorisation Group, TGA
ARCS Scientific Congress 2014
11 September 2014

Updates to AU Module 1 CTD
Revised structure
• 1.0 Letter of application
• 1.2 Application forms
• 1.3 Medicine information documents…
• 1.5 Specific requirements for different types…
• 1.7 Good manufacturing practice
• 1.8 Compliance with meetings and pre-submission
Electronic submission requirements for 1
prescription medicines AU eCTD Update

1.0 Correspondence
1.0 Correspondence 1.0 Letter of application
• 1.0.1 Cover Letter
• 1.0.2 Lifecycle management tracking table
• 1.0.3 Response to request for information
1
2
• 1.0.0 Electronic lodgement cover sheet
• 1.0.1 Letter of application
• 1.0.2 Responses to questions
• 1.0.2 Lifecycle management tracking table

1.1 Comprehensive table of contents
• Not applicable for eCTD applications and should not be submitted
• Also the Table of contents for 2.1, 3.1, 4.1 and 5.1 should not be included in eCTD format

1.2 Administrative information
1.2 Administrative information 1.2 Application forms
• 1.2.1 Application Forms
• 1.2.2 Pre-submission details
• 1.2.3 Patent certification
• 1.2.4 Change in sponsor
15/09/2014
4
• 1.2.1 Application Forms
• 1.2.2 Pre-submission details
• 1.2.3 Patent certification documents

1.3 Medicine information and labelling
1.3 Medicine information and labelling 1.3 Medicine information documents, packaging, and
• 1.3.1 Product information and package insert
• 1.3.1.1 Product information – clean
• 1.3.1.2 Product information – annotated
• 1.3.1.3 Package insert
• 1.3.2 Consumer medicines information
• 1.3.2.1 Consumer medicines information –
clean
• 1.3.2.2 Consumer medicines information –
annotated
• 1.3.3 Label mock-ups and specimens
5
• 1.3.1 Product information
– Marked-up copy of product information
– Package inserts
• 1.3.2 Consumer medicines information
• 1.3.3 Declaration concerning the use of human
embryos or human embryonic stem cells
• 1.3.4 Mock-ups or specimens of proposed Australian
labelling
labelling

1.5 Specific requirements for different types of applications
1.5 Specific requirements for different types
of applications
• 1.5.1 Literature-based submission documents
• 1.5.2 Orphan drug designation
• 1.5.3 Genetically modified organisms
consents
• 1.5.4 Additional trade name declarations
• 1.5.5 Co-marketed medicines declarations
• 1.5.6 Combination medicine consent
• 1.5.7 OTC product assurances
• 1.5.8 Analytical validation summary
6
• 1.5.1 Literature-based submission documents
• 1.5.2 Orphan drug: Copy of orphan drug designation
• 1.5.3 GMO: Consent from the OGTR
• 1.5.4 Additional Trade name declarations
• 1.5.5 Co-marketed medicine declarations
.
1.5 Specific requirements for different types of
applications

Master files and certificates of suitability
1.6 Master files and certificates of suitability 1.6 Drug and plasma master files and certificates of suitability of
• 1.6.1 Relevant external sources
• 1.6.2 Applicant’s declaration
• 1.6.3 Letters of access
7
• 1.6.1 Relevant drug and plasma master files
• 1.6.2 Applicant’s declaration
• 1.6.3 Letters of access
• 1.6.4 Certificates of suitability
monographs of the European pharmacopoeia

1.7 Good manufacturing practices
Removed
• The old section 1.7 Good manufacturing practices has been removed
• It has been added to the application form as a declaration

1.8 Information relating to pharmacovigilance
1.8 Information relating to pharmacovigilance 1.13 Information relating to pharmacovigilance
• 1.8.1 Pharmacovigilance systems
• 1.8.2 Risk management plan
9
• 1.13 Risk management plan for Australia

Foreign regulatory information
1.10 Overseas regulatory status 1.11 Foreign regulatory information
• 1.10.1 Overseas regulatory status
• 1.10.2 Product information from Canada, the
Netherlands, New Zealand, Sweden, UK and
USA, if applications submitted in these countries
• 1.10.3 Differences in the data set in applications
submitted in Australia, Canada, the Netherlands,
New Zealand, Sweden, UK and USA, if
applications submitted in these countries
Annex II Overseas evaluation reports
15/09/2014
10
• 1.11.1 Foreign regulatory status
• 1.11.2 Foreign product information
• 1.11.3 Data similarities and differences
• 1.11.4 Foreign evaluation reports

Regional content
Regional content
• Module 1 administrative and prescribing information
– The content and numbering of Module 1 for the AU is specified in the latest version of the CTD Module 1
Administrative information and prescribing information for Australia (to be updated soon)
– Document requirements for specific regulatory activities being submitted can be found in the eCTD
documents matrix.
• Module 2.3.R and 3.2.R regional information
– 2.3.R should provide a brief description of the information provided under 3.2.R
– Applicants should include the following information in Module 3.2.R, where appropriate:
 Process validation scheme for the drug product
 Certificates of suitability
 Risk of transmitting animal spongiform encephalopathy agents
 Supplier’s declarations regarding compliance with packaging standards and colouring standards.

Regional content
Regional content
• Node Extensions
– What are Node Extensions?
– A way of providing extra organisational
information to the eCTD.
– Visualised as an extra heading in the CTD
structure.
– Displayed as extra headings when the XML
backbone is viewed.
12
• Example: Grouping multiple files belonging to a single study
– 5312 (eCTD Section)
 Study ABC123
• Synopsis.pdf
• Report Body.pdf
• Discontinued Patient Listing.pdf
 Study XYZ321
• Synopsis.pdf
• Report Body.pdf
• Discontinued Patient Listing.pdf
– 537 CRFs
 Study ABC123
– Site 123
• CRF-123-0001.pdf
• CRF-123-0002.pdf
– Site 234
• CRF-234-0001.pdf
• CRF-234-0002.pdf

Regional content
• Node Extensions
– Consider the impact of changing node extension structures during the lifecycle
– Don’t user where ICH specified sub headings already exist
– Only use at the lowest level of the eCTD structure
– Use to group together multiple like documents
– Node extensions may be nested
– Node extensions content can be placed in separate sub folders
13
Regional content

Regional content
Regional content
• Study tagging files
– A structured solution to organizing studies in eCTD applications.
– Provides consistent structure for review and categorisation of clinical and nonclinical studies.
– Comprised of an XML Backbone file with category information and links to study content.
– Most useful when used with Clinical Studies.
– Content tags based on ICH E3 Guidance on the Structure of Clinical Studies.
– Predefined values for Species, Route of Administration, Duration and Type of Control.

Regional content
Regional content
• Study tagging files
– The TGA does not currently have any plans to mandate study tagging files (STFs) for evaluation purposes.
– Applicants wishing to reuse content submitted in other regions where STFs have been used can do so.
– If provided, STFs will be validated and must be conform to standards and specifications.
– Data pertaining to the number and size of ICH E3 16.3 CRFs and non ICH E3 documents will be collected
for informational purposes.

Regional content
Regional file formats
• Module 1 – Both PDF and XML have been designated as acceptable file formats for the AU Module 1.
– No structured exchange (XML) standards for content are currently defined
– These may be introduced in the future for content such as the lifecycle management tracking table,
application forms, etc.
– All PDF files included in an eCTD irrespective of the module should be v1.4, v1.5, v1.6 or v1.7 except
where a specific requirement for a later version is defined
– It is preferred that PDFs be generated from an electronic source. Signatures may be embedded as a
graphic file in the PDF text if desired.
• Modules 2 to 5 - No additional file formats are defined for Modules 2 to 5 other than those mentioned in the
ICH eCTD Specification Document.

Regional content
Use of electronic signatures
• Digital signatures can be used but only as an adjunct to any required written signatures.
• Scanned signatures would ordinarily be used where the documents make up part of the checksum of an
eCTD submission.

Regional content
Handling of empty or missing eCTD sections
• For new applications, including generic applications, detailed statements justifying the absence of data or
specific CTD sections should be provided in the relevant Quality Overall Summary and/or Nonclinical/Clinical
Overviews e.g. Module 2.3, 2.4, or 2.5.
• For a generic application, there is no need to provide a justification for content that is typically absent.
• Note that placeholder documents highlighting no relevant content should not be placed in the eCTD structure.

Regional content
Updating backbone attributes
• Updating ICH attributes
– Updating XML backbone attributes such as manufacturer during the eCTD lifecycle is possible.
– Consideration should be given regarding the impact of changing backbone attributes during the lifecycle.
– Changes can lead to a higher level of complexity in the cumulative view of a submission.
• Updating AU envelope information
– The AU envelope information can be updated during the lifecycle as is necessary to reflect changes in the
application metadata.

Regional content
Bookmarks, TOCs, and hyperlinks
• Bookmarks and/or TOCs make the review more efficient.
• The TGA recommends that documents with more than five pages and with multiple sections should provide a
Table of Contents, and/or if appropriate, a Table of Tables, Table of Figures, etc. on the first page of the
document.
• Hyperlinks are recommended when they would aid the evaluation in ways not already possible through the
use of the eCTD index.xml and document navigation aids.
• Applicants should consider when creating cross document hyperlinks that they can cause confusion later in
lifecycle and therefore be distracting for an efficient review.

Regional content
File reuse
• Applicants should make active use of file reuse.
• File reuse should be used when
– a file is submitted multiple times within one sequence,
– a file already submitted in an earlier sequence is being referenced again,
– or if a file submitted in another application is being referenced in a new application.
• Please note that the TGA is implementing a flat repository structure to make cross application referencing
possible.
– Links to content provided in other applications simply need to be directed out of the current application
structure and into the structure of the corresponding application.
– All application will be stored using the eSubmission Identifier to make cross referencing easily predictable
and possible.

Module 1 architecture
The AU Module 1 backbone file and style-sheet
• The Australian Module 1 is schema based instead of using a dtd.
• The Australian Module 1 eCTD backbone file comprises three main components:
– A fixed eXtensible Markup Language (XML) root element;
– The envelope elements; and
– The eCTD heading elements describing the actual files provided.
• Style-Sheet
– A standard style-sheet is provided that can be used to view content
– The style-sheet has been designed to display the complete Module 1
– The style-sheet is not part of the specification package
– eCTD applications can be submitted with or without the style-sheet
– The TGA will not be reviewing content using the style-sheet
– Its existence is not part of the validation criteria

Envelope elements
• What are Envelope Elements?
– Administrative information imbedded into a sequence which helps to identify and categorise the content,
also for automated processes.
XML Element Description Constraint Occurrence
Defined
List
esub-id eSubmission Identifier Mandatory Single
applicant Applicant Mandatory Single
aan Australian Approved Name(s) Mandatory Multiple
product-name Product Name Mandatory Multiple
artg-number ARTG Number Optional Multiple
sequence-description Sequence Description Mandatory Single X
sequence-number Sequence Number Mandatory Single
related-sequence-number
Related Sequence Number Optional Single
reg-activity-lead Regulatory Activity Lead Mandatory Single X
sequence-type Sequence Type Mandatory Single X
AU eCTD Update 23

Envelope elements: defined lists
• The defined lists are provided and maintained as separate XML files
• Each file contains a standard set of codes for the corresponding envelope element.
• Codes have been implemented to reduce validation issues
• The code definition files contain a version number, version date and coded values as well as plain texts for
each value.
• Only the plain text value is shown to the reviewers in the review system.
• Defined lists have been created for
– Sequence Description
– Regulatory Activity Lead
– Sequence Type
• Defined lists will be maintained on the TGA website

Envelope elements: sequence description
• The sequence description defined list of codes and values is available from TGA website. Applicants should
refer to this list for current list values.
• There are 4 types of sequence description approaches
1. Some values can be used without further information
2. Others will require the description to be combined with a date
3. In the example with the PSUR, both the start date and the end date will have to be entered
4. Finally, some descriptions will need additional information added in the form of a brief description (brief -
under 40 characters)

Envelope elements: regulatory activity lead and sequence type
• Regulatory Activity Lead
– The regulatory activity lead defined list of codes and values are on TGA website.
– The code for “Prescription” is reg-act-lead-6 as specified in the defined list
Note that the code version must be specified as an attribute code-version of the reg-activity-lead element.

Envelope elements: regulatory activity lead and sequence type
Sequence type
• The sequence type defined list of codes and values is available from TGA website. Applicants should
refer to this list for current list values.
• The code for “New chemical entities” is seq-type-1 as specified in the defined list
Note that the code version must be specified as an attribute code-version of the sequence-type element.
15/09/2014

Heading elements
• What are Heading Elements?
– Each specified section of the eCTD is associated with a heading element which is used to identify and
organise the content associated with that section.

Heading elements
Section ID Business Terminology XML-Element
1.0 Correspondence m1-0-correspondence
1.0.1 Cover letter m1-0-1-cover
1.0.2 Lifecycle management tracking table m1-0-2-tracking-table
1.0.3 Response to request for information m1-0-3-response
1.2 Administrative Information m1-2-admin-info
1.2.1 Application forms m1-2-1-app-form
1.2.2 Pre-submission details m1-2-2-pre-sub-details
1.2.3 Patent certification m1-2-3-pat-cert
1.2.4 Change in sponsor m1-2-4-change-sponsor
1.3 Medicine information and labelling m1-3-med-info
1.3.1 Product information and package insert m1-3-1-pi
1.3.1.1 Product information - clean m1-3-1-1-pi-clean
1.3.1.2 Product information - annotated m1-3-1-2-pi-annotated
1.3.1.3 Package insert m1-3-1-3-pack-ins
1.3.2 Consumer medicines information m1-3-2-cmi
1.3.2.1 Consumer medicines information - clean m1-3-2-1-cmi-clean
1.3.2.2 Consumer medicines information - annotated m1-3-2-2-cmi-annotated
1.3.3 Label mock-ups and specimens m1-3-3-mockup
1.4 Information about the experts m1-4-experts
1.4.1 Quality m1-4-1-quality
1.4.2 Nonclinical m1-4-2-nonclinical
1.4.3 Clinical m1-4-3-clinical
1.5 Specific requirements for different types of applications m1-5-specific
1.5.1 Literature-based submission documents m1-5-1-lit-based
1.5.2 Orphan drug designation m1-5-2-orphan
1.5.3 Genetically modified organisms consents m1-5-3-gmo
1.5.4 Additional trade name declarations m1-5-4-trade-name
1.5.5 Co-marketed medicines declarations m1-5-5-co-marketed
1.5.6 Combination medicine consent m1-5-6-comb-med
1.5.7 OTC product assurances m1-5-7-prod-assurance
1.5.8 Analytical validation summary m1-5-8-analyt-val-sum
1.6 Master files and certificates of suitability m1-6-master-files
1.6.1 Relevant external sources m1-6-1-ext-sources
1.6.2 Applicant's declaration m1-6-2-app-decl
1.6.3 Letters of access m1-6-3-loa

Heading elements
1.7 Compliance with meetings and pre- submission processes m1-7-compliance
1.7.1 Details of compliance with pre-submission meeting outcomes m1-7-1-pre-sub
1.7.2 Details of any additional data to be submitted m1-7-2-add-data
1.7.3 Declaration of compliance with pre-submission planning form and planning letter m1-7-3-planning
1.8 Information relating to pharmacovigilance m1-8-pv
1.8.1 Pharmacovigilance systems m1-8-1-pv-systems
1.8.2 Risk management plan m1-8-2-risk
1.9 Summary of biopharmaceutic studies m1-9-biopharm
1.9.1 Summary of bioavailability or bioequivalence study m1-9-1-ba-be
1.9.2 Justification for not providing biopharmaceutic studies m1-9-2-justification
1.10 Information relating to paediatrics m1-10-paediatrics
1.11 Foreign regulatory information m1-11-foreign
1.11.1 Foreign regulatory status m1-11-1-status
1.11.2 Foreign product information m1-11-2-pi
1.11.3 Data similarities and differences m1-11-3-similarities
1.11.4 Foreign evaluation reports m1-11-4-eval-reports
1.12 Antibiotic resistance data m1-12-antibiotic

Node extensions and leaf elements
• Structures beyond the heading elements can be defined through node extension elements.
• Content for each heading element is provided through leaf elements.
• Wherever a leaf element is allowed in the schema, a node-extension element is also allowed.
• Allowing node-extension structure is in compliance with general ICH eCTD specifications.
• The node extension title element and leaf title element should be short, precise and informative.
– Information already categorized by heading elements need not be repeated.
– The most important identifying information should be placed at the beginning to prevent reviewers from
having to scroll to the end of the title.

Validation criteria
eCTD v0.90
• No major new or unusual validation criteria developed
• Other regions were analysed, compared and adopted if suitable
NeeS v1.0
• Adoption of EU Specifications
• File and folder names for AU M1 defined
• Strict adherence moving forward
• Applications under old structure still accepted, tolerance for file and folder names

Items worth noting
Validation criteria
• Files and Folders
– There are no naming conventions being validated
• ICH Backbone
– File Reuse - Information is collected about references outside the application and sequence as well as
multiple references to a file within a sequence
• AU Regional
– File Reuse
– Cover Letter must be New
– Information is collected when Application Form is not New
• STF
– If provided, will be validated and must be valid

Validation tools
Most vendors offer free basic versions of their validation tools
• No excuses for submitting applications that do not pass technical validation
• Make sure you validate on the media being submitted
• Validation should be limited to criteria specified by the TGA
– Some vendors provide extended profiles, these should not be provided with the application
• List of validation tools will be provided on the eSubmission Website as vendors provide evidence that they
can sufficiently validate the TGA requirements
• Current free version of validation tool being used by the TGA can be found at:
– http://www.lorenz.cc/esolutions/eValidator/ (Link also provided on TGA eSubmission webpage)

Additional guidance documentation
AU guidance
• AU Regional Specification and Validation Criteria - source document for Module 1 elements, envelope
attributes, eCTD and NeeS Validation criteria and NeeS naming conventions for the AU Module 1.
• AU Schema - structure, content and semantics of the AU eCTD Module 1.
• AU eCTD Document Matrix - A summary of eCTD Module 1 document requirements for each application
type.
• AU Module 1 Comparison of CTD v2.2 and eCTD - A summary document on the content requirements
specific to the new eCTD structure for applications submitted in eCTD format. This is an interim document to
be used in connection with the CTD Module 1: Administrative information and prescribing information for
Australia until that document is updated.
• AU eCTD FAQ - Frequently asked questions on the Australian eCTD.

Additional guidance documentation
ICH guidance
• ICH eCTD Specification and Related Files - ICH links to specifications and related files including change
control process, change request forms and their Q&A document.
• ICH Electronic Common Technical Document Specification - a harmonised technical solution to implementing
the CTD electronically.
• ICH The eCTD Backbone File Specification for Study Tagging Files - a structured solution to organizing study
in eCTD applications.

Submitting eCTD
Obtaining the eSubmission Identifier
• The sponsor should submit a written request to the TGA via email (eSubmissions@tga.gov.au) to obtain an
eSubmission identifier.
• An application for an eSubmission identifier will need to be made for each dossier if the sponsor wishes to
provide multiple dossiers for the same active ingredient.
• A request for an eSubmission identifier should include:
– the applicant’s name as listed in the eBS client database
– Australian Approved Names (or proposed AANs)
– Description of Application.

Submitting eCTD
• The cover letter should also be provided in paper to serve as a transmission letter
• The cover letter should include:
– The eSubmission identifier in the subject line
– A description of the electronic submission
– A statement that the submission is virus free
– The regulatory and information technology points of contact for the submission; and
– A reference to the validation report
• The letter should not contain any scientific information
38
The cover letter as transmission letter
15/09/2014

Submitting eCTD
Validation reports
• Indicate which validation tool and version was used in cover letter
• Address any issues found in the validation report in the cover letter
• An electronic copy of the validation report created should be submitted
• A folder should be created in the application folder named after the eSubmission identifier with the naming
convention of the sequence number followed by validation-report
– e.g. “0000-validation-report”.
• The validation report should be limited to only items listed in the validation criteria, additional checks should
not be included.

The pilot
Timelines
• Publishing technical documents on www.tga.gov.au - June 2014
• Workshop on eCTD submissions - 3 July 2014
• ARCS Congress session - 11 September 2014
• Comments close on initial documents - 3 November 2014
• Assessment of readiness for eCTD submissions - February 2015
• Updates will be published on the web during the pilot period

The pilot
Scope of samples being sought
• Working with industry representatives to identify suitable eCTD pilot submissions
• Testing various aspects of system before full adoption in 2015.
• Looking to test the following application types:
– new chemical entity
– major variations to a prescription medicine (both with and without baseline)
– generic medicine.
– submissions prepared with different publishing tools
• Please contact esubmissions@tga.gov.au if you wish to be involved with the pilot program.
1

Electronic submission requirements for prescription medicines - AU eCTD update

Electronic submission requirements for prescription medicines - AU eCTD update

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