TGA presentations given at ARCS eCTD workshop, 16 December 2014

1. eSubmissions in Australia
Part 2
Dr John Donohoe Director, Knowledge Management Section Office of Medicines Authorisation 16 December 2014

2. Regional Content
•
Module 1 administrative and prescribing information
•
Module 2.3.R and 3.2.R regional information
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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
§
Certified Product Details
§
Supplier’s declarations regarding compliance with packaging standards and colouring standards. eSubmissions in Australia 1

3. 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.
•
Node-extension structure is in compliance with general ICH eCTD specifications
•
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 eSubmissions in Australia
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4. Node Extensions and Leaf Elements
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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.
•
The optional node-extension element contains a single mandatory title element, followed by at least one leaf element.
•
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.
eSubmissions in Australia
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5. Node Extensions
•
Node Extension structures should be considered and used where needed to assist reviewers
•
Consider the impact of changing node extension structures during the lifecycle
•
Don’t use 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
eSubmissions in Australia
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6. Leaf Titles
•
The display name given to a document and will be shown to the evaluator
•
An evaluator never sees the file/folder names in the file structure
•
Leaf titles should not include:
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file extensions, e.g. appendix1.pdf
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hyphens or underscores, e.g. copy-certification.pdf
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eCTD section number.
The eCTD application has “life cycle” and contains the history of all your submissions! eSubmissions in Australia 5

7. Study Tagging Files
•
A structured solution to organizing studies in eCTD applications providing a 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.
•
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.
•
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. eSubmissions in Australia
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8. Regional File Formats
•
Module 1 – Both PDF and XML have been designated as acceptable file formats for the AU Module 1.
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No structured exchange (XML) standards for content are currently defined
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These may be introduced in the future for content such as the lifecycle management tracking table, application forms, etc.
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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
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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. eSubmissions in Australia
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9. Use of Electronic Signatures
•
Currently the use of digital signatures for electronic submissions is not fully supported within the TGA.
•
Scanned signatures would ordinarily be used where the documents make up part of the checksum of an eCTD submission.
eSubmissions in Australia
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10. 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. eSubmissions in Australia
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11. Updating Backbone Attributes
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Updating ICH attributes
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Updating XML backbone attributes such as manufacturer during the eCTD lifecycle is possible.
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Consideration should be given regarding the impact of changing backbone attributes during the lifecycle.
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Changes can lead to a higher level of complexity in the cumulative view of a submission.
•
Updating AU envelope information
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The AU envelope information can be updated during the lifecycle as is necessary to reflect changes in the application metadata.
eSubmissions in Australia
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12. File Reuse
•
TGA accepts and encourages applicants to make active use of file reuse.
•
Applicants should not submit the same document multiple times.
•
File reuse should be used when
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a file is submitted multiple times within one sequence,
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a file already submitted in an earlier sequence is being referenced again,
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or if a file submitted in another application is being referenced in a new application.
•
TGA is implementing a flat repository structure to make cross application referencing possible.
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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.
eSubmissions in Australia
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13. 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:
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A fixed eXtensible Markup Language (XML) root element;
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The envelope elements; and
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The eCTD heading elements describing the actual files provided.
•
Style-Sheet
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A standard style-sheet is provided that can be used to view content
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The style-sheet has been designed to display the complete Module 1
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The style-sheet is not part of the specification package
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eCTD applications can be submitted with or without the style-sheet
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The TGA will not be reviewing content using the style-sheet
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Its existence is not part of the validation criteria eSubmissions in Australia
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14. Module 1 Architecture
XML Root Element
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All Australian Module 1 backbone files prepared for the TGA will contain the standard XML root element
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The required text includes an XML declaration and the root element tga_ectd with its attributes linking the XML file to the XML definition prepared by the TGA
•
Without style-sheet:
•With style-sheet: eSubmissions in Australia
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15. 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 eSubmissions in Australia
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16. Envelope Elements: Defined Lists
•
The defined lists are provided and maintained as separate XML files
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Each file contains a standard set of codes for the corresponding envelope element.
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Codes have been implemented to reduce validation issues
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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
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Sequence Description
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Regulatory Activity Lead
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Sequence Type eSubmissions in Australia
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17. Envelope Elements: Sequence Description
•
The sequence description defined list of codes and values is available from http://tga.gov.au/downloads/sequence-description.xml. Applicants should refer to this list for current list values.
•
There are 4 types of sequence description approaches
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Some values can be used without further information
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Others will require the description to be combined with a date
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In the example with the PSUR, both the start date and the end date have to be entered
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Finally, some descriptions will need additional information added in the form of a brief description (brief – under 40 characters) eSubmissions in Australia
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18. Envelope Elements
Sequence Description Example 1
Some values can be used without further information e.g. Initial.
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The code for “Initial” is seq-desc-2 as specified in the defined list
–
Note that the code version must be specified as an attribute code-version of the sequence-description element. eSubmissions in Australia
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19. Envelope Elements
Sequence Description Example 2
Others will require the description to be combined with a date e.g. Response to Screening Clarification Request – 2014-03-30.
–
The code for a response to a screening clarification request is seq-desc-5 as specified in the defined list
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Response to Screening Clarification Request - {date:d}
–
A date is required as additional data. The name of the placeholder is date. It requires an actual value in date format (because of the letter d following the colon).
eSubmissions in Australia
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20. Envelope Elements
Sequence Description Example 3
In the example with the PSUR, both the start date and the end date will have to be entered e.g. PSUR for Period of 2015-01-01 to 2015-06-30.
–
The code for “PSUR” is seq-desc-20 as specified in the defined list
–
PSUR for Period of {from-date:d} to {to-date:d}
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Two placeholders have been specified. The first one is named from-date and the second one is named to-date eSubmissions in Australia
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21. Envelope Elements
Sequence Description Example 4
Finally, some descriptions will need additional information added in the form of a brief description (brief – under 40 characters) e.g. Uncategorised, DESCRIPTION.
–
The code for “uncategorized” is seq-desc-24 as specified in the defined list
–
Uncategorised, {description:s}
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The name of the placeholder is description. It requires an actual value in plain text format which is indicated by the letter “s” following the colon. eSubmissions in Australia
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22. Envelope Elements
Regulatory Activity Lead
The regulatory activity lead defined list of codes and values is managed at http://tga.gov.au/downloads/reg-activity-lead.xml. Applicants should refer to this list for current list values.
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. eSubmissions in Australia
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23. Envelope Elements
Sequence Type
The sequence type defined list of codes and values is available from http://tga.gov.au/downloads/sequence-type.xml. 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. eSubmissions in Australia
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24. 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. eSubmissions in Australia
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25. 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
Section ID
Business Terminology
XML-Element
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
eSubmissions in Australia
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26. Heading Elements
Section ID
Business Terminology
XML-Element
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
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27. Module 1 Architecture
Files and Folders
•
Naming conventions for the content files are irrelevant for electronic review.
•
All content must be referenced by the appropriate XML files for efficient navigation.
•
Applicants should concentrate on providing precise but informative leaf titles to aid reviewers.
Folder
File
Description
e123456
Application folder with eSubmission identifier e.g. e123456
0000
Sequence folder with four digit sequence number e.g. 0000
index.xml
Index file in accordance with ICH
index-md5.txt
MD5 checksum in accordance with ICH
m1
Content folder for Module 1 documents in accordance with ICH
au
Australia country specific folder
au-regional.xml
Australia regional index file for Module 1
m2
Content folder for Module 2 documents in accordance with ICH
m3
Content folder for Module 3 documents in accordance with ICH
m4
Content folder for Module 4 documents in accordance with ICH
m5
Content folder for Module 5 documents in accordance with ICH
util
Util folder in accordance with ICH
dtd
DTD and schema folder in accordance with ICH
au-regional.xsd
Australia regional backbone schema for Module 1
xlink.xsd
W3C schema for XLink 1.1 (referenced from au-regional.xsd)
xml.xsd
W3C schema for XML namespace (referenced from au-regional.xsd)
ich-ectd-3-2.dtd
ICH DTD for Modules 2 to 5
style
Style sheet folder in accordance with ICH (optional)
ectd-2-0.xsl
ICH style sheet for Modules 2 to 5 (optional)
au-regional.xsl
Style sheet for Australian regional backbone (optional)
0000-validation-report
Comprehensive output from an eCTD validation tool eSubmissions in Australia
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28. The Final Take Away
Consider Your Audience:
•If you were the evaluator and you are not familiar with the submission, could you easily navigate the submission and do an efficient review?
•Perform an overall QC after compiling the submission.
•Navigate the submission using eCTD TOC tree, leaf titles, links, and bookmarks keeping the evaluator in mind.
•Use a QC process or checklist to help ensure submissions don’t contain formatting issues.
•Good planning and being proactive can help you avoid the need to respond to queries, send resubmissions, and send additional corrective submissions to fix formatting issues! eSubmissions in Australia 27