eSubmissions in Australia Part 2 Dr John Donohoe Director, - PowerPoint PPT Presentation

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

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

Node Extensions • Example: Grouping multiple files belonging to a single study • A way of providing extra organisational – 5312 (eCTD Section) Study ABC123 § information to the eCTD. • Synopsis.pdf • Visualised as an extra heading in the • Report Body.pdf • Discontinued Patient Listing.pdf CTD structure. Study XYZ321 § • Synopsis.pdf • Displayed as extra headings when the • Report Body.pdf XML backbone is viewed. • Discontinued Patient Listing.pdf • Node-extension structure is in – 537 CRFs compliance with general ICH eCTD Study ABC123 § ‒ Site 123 specifications • CRF-123-0001.pdf • CRF-123-0002.pdf ‒ Site 234 • CRF-234-0001.pdf eSubmissions in Australia 2 • CRF-234-0002.pdf

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. • 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 3

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 4

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: – file extensions, e.g. appendix1.pdf – hyphens or underscores, e.g. copy-certification.pdf – eCTD section number. The eCTD application has “life cycle” and contains the history of all your submissions! 5 eSubmissions in Australia

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 6

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. eSubmissions in Australia 7

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 8

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 9

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. eSubmissions in Australia 10

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 – 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. • 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. eSubmissions in Australia 11

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 eSubmissions in Australia 12

Module 1 Architecture XML Root Element • All Australian Module 1 backbone files prepared for the TGA will contain the standard XML root element • 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 13

Envelope Elements • What are Envelope Elements? – Administrative information imbedded into a sequence which helps to identify and categorise the content, also for automated processes . Defined XM L Element Description Constraint Occurrence 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 14