eSubmissions in Australia Part 1

Dr John Donohoe Director, Knowledge Management Office of Medicines Authorisation Market Authorisation Group eCTD Workshop – Melbourne 16 December 2014

The Road to eCTD • Transition to CTD – 2004

• Implementation of NeeS – 2011

• Implementation of eCTD capability – 2014

– Revised AU Module 1

Past Activities

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eCTD at TGA • Integration of business processes

– Records management, application management , evaluators

– Total Lifecycle Management of products

• Capacity and capability building – Support, training for internal and external

staff – Updating guidance, processes, services

Update on progress with the Pilot phase

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The Road to eCTD Past Activities – revised AU Module 1

• Alignment with EU – revised structure • Separate lifecycle tracking table • Moved to application form

- human embryos/embryonic stem cells - GMP information - individual patient data

• Used global terminology where possible e.g. changed “Overseas” to “Foreign” • Flexibility for non-prescription medicines

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The Road to eCTD • Expanded internal training programme • Lessons from pilot submissions • Alignment of existing business process • Review of consultation process • Updates to specifications and system

configuration • February 2015 – Assessment of experience

with, and readiness for, eCTD

Current Activities and Next Steps

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The Road to eCTD Some numbers…

• 1231 NeeS Submissions as of June 2014 • 1856 Approvals in 2013 for Prescription Category 1 and Category 3 Applications* • 2808 Approvals in 2013 for Over the Counter Applications* • Developing capacity to evaluate electronically • 7 eCTD submissions received in eCTD pilot

* Numbers taken from the TGA Half-yearly performance reports, July to December 2013, Published May 2014

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The Road to eCTD The eCTD Pilot Phase

• Working with applicants to identify suitable eCTD submissions for the pilot phase • Developing various aspects of system • Looking for a range of application types:

– new chemical entity – major variations to a prescription medicine (both with and without baseline) – generic medicine – submissions prepared with different publishing tools – prescription / non-prescription medicines – master files

• Please contact esubmissions@tga.gov.au if you wish to discuss being involved with the pilot phase

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The eCTD Pilot Current Business Protocol for Submitting an eCTD • Participation in pilot phase • Obtaining the eSubmission Identifier – submit written request to eSubmissions@tga.gov.au • The Cover Letter – Paper copy should be submitted until Portal is implemented • Validation Reports – Electronic copy should be submitted in e.g. “0000-validation-report” folder • Expected Structure of Submitted Media

– Submit in folder named after eSubmission Identifier. – Preference is that entire application should not span multiple devices

• Media Formats – flexible • Feedback on Validation of Application

– TGA will inform applicants if problems are experienced during the upload of an eCTD sequence. – Confirmation of delivery is through the courier company eSubmissions in Australia 7

eCTD Document Matrix TGA eCTD Document Matrix

Category 1 / Category 2

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1.0 Correspondence 1.0.1 Cover letter E E E E E E E E E E E E 1.0.2 Lifecycle management tracking table E E E E E E E E E E E E 1.0.3 Response to request for information NE NE NE NE NE NE NE NE NE NE NE NE 1.2 Administrative Information 1.2.1 Application form E E E E E E E E E E E E 1.2.2 Pre-submission details E E E E E E E E E E E P 1.2.3 Patent certification P P P P P P P P P P P NE 1.2.4 Change of sponsor NE NE NE NE NE NE NE NE NE NE NE NE 1.3 Medicine information and labelling 1.3.1 Product information and package insert 1.3.1.1 Product information - clean E E E E E E E E E E E E 1.3.1.2 Product information - annotated P P E P E E E E E E E E 1.3.1.3 Package insert P P P P P P P P P P P P 1.3.2 Consumer medicines information 1.3.2.1 Consumer medicines information - clean E E E E E E E E E E E P 1.3.2.2 Consumer medicines information - annotated P P E P E E E E E E E P 1.3.3 Label mock-ups and specimens E E E E NE E E E E P P NE 1.4 Information about the experts 1.4.1 Quality E E E E P E P P P P P P 1.4.2 Nonclinical E E E E P P P P P P P P 1.4.3 Clinical E E E E P W P P P P P P 1.5 Specific requirements for different types of applications 1.5.1 Literature-based submission documents P P P P P P P P P P P P 1.5.2 Orphan drug designation P P P P P P P P P P P NE 1.5.3 Genetically modified organisms consents P P P P P P P P P P P NE

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Building Regulatory Activities and Submission Numbering Regulatory Activity The entire group of sequences supporting a specific regulatory activity Identified/established by the submission type e.g., an original application and all its amendments leading to approval Sequence-number Must be unique within the application Incremented for each new submission to an application

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eCTD: General Information & Advice

• Once an eCTD always an eCTD means don’t send non-eCTD or paper to an eCTD application

• Don’t send files outside the eCTD sequence folder • Don’t send files that are not referenced in the correct, appropriate eCTD

backbone (index.xml, au-regional.xml) • Develop checklists to ensure the submission is complete

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Always Check Your Submission • Quality check (QC) your submission prior to submitting it • Use checklists and establish a good, efficient QC process • Ensure the media contains the submission • Ensure no files are truncated • Check submission using a validation tool

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eCTD Validation • Use an eCTD Validator to identify technical problems with your submission

BEFORE sending it to TGA • Do not ignore errors • High error content will result in the rejection of your submission

– lost time and $ • Current eCTD Validation Specifications are available on the TGA eCTD

webpages

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Rejections

Submissions that are technically deficient or otherwise cannot be processed: • Cannot determine the correct application number/type • High level of validation errors • Duplicate eCTD sequence numbers • Non-allowed file types eg .exe

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Font embedding • The intent is to ensure evaluator can access all the information in your

submission • Use the “standard fonts” and there is no need to embed, these fonts are always

available on the evaluator’s PCs • If you use “non-standard fonts” you should fully embed the font.

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PDF Errors • Create text-based PDFs from source documents • Avoid scanning documents or embedding scanned documents • Use validated OCR if you must scan a document

– Use only standard fonts – Fully embed all non-standard fonts if used

• Initial View Settings – Set the Navigation Tab to open to “Bookmarks Panel and Page.” If there are

no bookmarks, set the Navigation Tab to “Page Only.” Page Layout and Magnification should be set to “Default.”

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PDF Errors • Navigation

– Provide bookmarks and a hyperlinked TOC – Use hypertext links throughout the body of the document to link to: § supporting annotations § related sections § references § appendices § tables, or § figures that are not located on the same page as the narrative text.

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Improving PDF Documents • Include page numbers • Include document date • Avoid use of scanned documents:

– Limits ability to text search – Can copy only as a ‘graphic’

• Hypertext links: Within a document and between documents in an application – May be challenge to create, QC and maintain, but – Very useful to the evaluator e.g., Links to Pharm/Tox studies for qualification of

impurities in Module 4

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Bookmarks, TOCs, and Hyperlinks

• Bookmarks and/or TOCs make the review more efficient. • 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.

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Hypertext Link Issues • Insufficient hyperlinks (none or not enough) • Hypertext links go to incorrect destination or don’t work (destination set to same

page) • References aren’t descriptive enough for an evaluator to find the information if the

link doesn’t work or doesn’t exist • The Table of Contents (TOC) isn’t linked • For inter-document links, it’s preferred that the link opens the target document in a

new window

Evaluators appreciate links instead of searching for a reference (table, figure, document, section, etc.)

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Hypertext Link Recommendations Provide linked references in documents (tables, figures, images, sections, inter-document links, etc.)

– Provide clear, concise references. – Use blue text links (preferred) or blue box links – Providing linked references from the cover letter is helpful – Provide linked TOCs in documents – Set links to Inherit Zoom – Check your links before submitting

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Document Settings • Initial View Settings for PDFs: • Navigation tab set to open to bookmarks, panel and page • Page Layout set to default • Magnification should be set default

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Operator Attribute Issues Issue: Incorrect use of eCTD operator attributes (i.e., fail to use/apply the replace operator resulting in multiple version of the same document when there should only be one current version)? Is there only one current version? Will the evaluator expect to see and know why there are multiple current versions? Will evaluators know the difference between each current version from the leaf title? Solution: If the answer is “no”, you may not be using eCTD operator attributes correctly or you need to use leaf titles or another method to indicate the difference for the multiple current versions of a document.

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Document Granularity Issues Issue: You are providing many one page bioequivalence summary table documents when it would probably be more efficient for an evaluator to have one document with a TOC, bookmarks and links Solution: If it makes sense to combine one and two page documents into a single document in an eCTD section, then do it and provide a linked TOC with bookmarks.

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eCTD at TGA Highlights of the AU Validation Criteria

• There are no naming conventions being validated • File Reuse - Information is collected about references outside the application and

sequence as well as multiple references to a file within a sequence • Cover Letter must be New • Lifecycle Tracking Table must be Replace • Application Form should be New • Risk Management Plan should be Replace • STF accepted but if provided, will be validated and must be valid

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eCTD at TGA • Continuity planning

– Commitment to existing registration timelines – Assistance for applicants and sponsors

• Assessment of progress – First assessment point – Feb 2015 – Continue accepting target application types to the pilot phase and beyond on

a case-by-case basis • Review of technical documentation

– Review of stakeholder comment – On-going development of supporting documentation

• Ongoing communication with stakeholders eSubmissions in Australia

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Future Direction for eSubmissions • Readiness assessment in February 2015 will determine next steps • Revised technical documents • eSubmissions Portal and Automated Processes • Regulated Product Submissions Standard

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Stay informed about eCTD • Website:

http://www.tga.gov.au/australian-ectd-submissions

• email: eSubmissions@tga.gov.au

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