eCTD in Australia and Experience in the Pilot Programme Update on the latest Australian eCTD specification

Dr John Donohoe Medicines Authorisation Branch Market Authorisation Division, TGA ARCS Scientific Congress 2015

6 May 2015

Implementing eCTD Overview

• Late 2014 the TGA commenced a pilot of eCTD format submissions using Version 0.9 of the Australian eCTD Module 1 and Regional Specification to validate, review and process electronic applications.

• April 2015 TGA published the final version of the Australian eCTD specifications: Australian eCTD specification: Module 1 and regional information, Version 3.0.

• Regulatory submission publishing software packages can now incorporate AU eCTD specifications. • Key dates

Submissions in version 3.0 will be valid from 1 June 2015 onwards Submissions in version 0.9 will not be valid after 31 December 2015 From 1 January 2016 you must use version 3.0 for your eCTD submissions

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What happens to your submission when it arrives at TGA? (I) 1. TGA Records Management team checks if your eCTD submission meets the validation criteria

• It meets the validation criteria

− The submission goes to the relevant TGA business unit who will schedule and manage the registration process

− Reduces administration effort − Improves the quality of the dossier − Checks completeness of the submission

• It does not meet the validation criteria

− TGA Records Management team checks why the submission has failed validation. Depending on the type of errors and warnings, we either progress the submission to the relevant business unit or send it back to you to address the validation issues

• We recommend you validate your submission with validation software prior to sending it to the TGA.

(See www.tga.gov.au for software suggestions)

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What happens to your submission when it arrives at TGA? (II)

2. An evaluator navigates your electronic dossier using hyperlinks and bookmarks within the docuBridge® review tool:

• It is therefore vitally important that you manage the granularity of the application and maintain your hyperlinks and bookmarks

Advantages for Sponsor and the TGA:

• More searchable than paper • Eliminates storage and distribution of paper • Provides lifecycle management • Locating, navigating and evaluating submissions is easier • Provides a collaborative environment for evaluators

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Reviewing an electronic dossier – Realities (I) Tips to avoid common problems (PDFs) Following these tips makes it easier for evaluators… and therefore you! • Optimise your PDF documents

– Too many small documents? • Combine one and two page documents into a single document in an eCTD section • Provide a linked TOC (table of contents) with bookmarks

– Ensure changes in files are always apparent – Make your PDF documents ‘text searchable’ – Generate your PDF documents from electronic source documents – Scanned documents will limit the ability to text search because it copies the document as a graphic

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Reviewing an electronic dossier – Realities (II) Tips to avoid common problems (leaf titles) Following these tips makes it easier for evaluators… and therefore you! • Better leaf titles

– Avoid excessively long leaf titles – Ensure leaf titles are unique – Make your leaf title concise, meaningful and related to the file content

• If your leaf title reflects the document’s content someone unfamiliar with the submission should be able to understand the document content.

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Reviewing an electronic dossier – Realities (III) Tips to avoid common problems (operator attributes) Following these tips makes it easier for evaluators… and therefore you! • Use the correct eCTD operator attributes.

Example: – Failure to apply the ‘Replace’ operator will result in multiple versions of the same document. – This causes confusion for the evaluator:

• Is there only one current version? • Why there are multiple current versions? • Will the leaf title tell me anything?

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eSubmission Identifier You will need an eSubmission Identifier The eSubmission Identifier is fundamental for the lifecycle management of your product • The eSubmission Identifier is unique for a sponsor / active ingredient

– Six digits plus a letter e.g. e123456 or n765432 ‘n’ for NeeS ‘e’ for eCTD

• Remains valid throughout entire lifecycle of product • To obtain one, send an email to esubmissions@tga.gov.au with:

– Applicant’s name – Name of medicine or subject of Master File – Description of the Application (application type, dosage form) if a medicine – Name and address of manufacturing site if a Master File.

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Module 1.0.2: Lifecycle management tracking table

Sequence Sequence Type Sequence Description Related Sequence

0000 Baseline Reformat 0000 0001 C-Extension of Indication of COPD Initial 0001

0002 Supplementary information Response to Request for Information 0001

0003 H-Minor Variation, Not Resulting in a New Register Entry Initial 0003

0004 F-Major Variation—New Strength Initial 0004

• All sequences must contain an updated table: – Omission will cause a validation error (for an eCTD submission) – Its use is recommended for NeeS

• Use Defined lists for Sequence type and Sequence description

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Hyperlinks and bookmarks (I) Be consistent using hyperlinks and bookmarks Following these tips makes it easier for evaluators… and therefore you! • Their use should be well thought out:

– be used throughout a submission – be used in all tables, figures, publications, and appendices from the table of contents – be indicated typographically with blue text or a blue box around the text – This will aid the evaluator to efficiently navigate to annotations, related sections, publications, appendices,

tables, and figures not located on the same page. • Overuse can lengthen the evaluation process because it can create confusion for evaluators. • Underuse can lengthen the evaluation process because the evaluator will need to search and find the

relevant information or may find the wrong information.

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Hyperlinks and bookmarks (II) External Links

Following these tips makes it easier for evaluators… and therefore you! • Links to external destinations (not web or email) will result in a validation error

• Links to web or email destinations are retrieved for information at validation

– Some links to a web page "www.*****" (such as sponsors own websites) or e-mail addresses "*****@****" are acceptable for some labelling documents and literature references

• External links to information pertinent to the evaluation process need to be submitted

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Hyperlinks and bookmarks (III) Following these tips makes it easier for evaluators… and therefore you! • TGA does not routinely require the submission of individual patient data • We do require complete study reports

– The ICH guideline on the Structure and Content of Clinical Study Reports describes several appendices that “where permitted by the regulatory authority, some of the following appendices need not be submitted with the report but need to be provided only on request.”

• Appendices 16.1 – 16.3 should routinely be submitted – 16.1 Study information – 16.2 Patient data listings – 16.3 Case report forms – 16.4 Individual patient data listings.

• If dossiers have been previously submitted to other agencies and appendices have been added or deleted to the TGA version, sponsors must ensure that hyperlinks in the dossier to these appendices have also been added or deleted.

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Hyperlinks and bookmarks (IV) Following these tips makes it easier for evaluators… and therefore you! Considerations • Does the bookmark name indicate the bookmark’s destination/content? • Is the bookmark too long? • Are bookmarks provided for the TOC items? • Does the bookmark match the description/title showing on the TOC? • Will someone who is unfamiliar with the application know what content they’ll see before they click on the

bookmark? • Are bookmarks set to Inherit Zoom?

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Key technical highlights v3.0 • Baseline sequence • Change of sponsor • Pre-Advisory Committee Response • Regulatory Activity is Rejected or Withdrawn

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Baseline sequence Sequence type = Baseline Sequence description = Reformat

• Is a resubmission of currently valid documents already provided in another format • Always a separate sequence • Never includes new regulatory activities • Sponsor must verify:

– formatting is the only change to the previous dossier(s) – no amendments to content – all the information was in the previous version(s) of the dossier – any omissions do not cause the content to be misleading.

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Change of sponsor – what to do (I) Sponsor F

e000111 Sponsor P

e000222 Sponsor Y

e000333 Activity/Task

Product A; Product B; Product C; Product D

0001 Application for Products A, B, C and D from Sponsor F

0002 A regulatory activity or notification

Product A; Product B Product C; Product D

0003 Sponsor P submits first sequence as 0003 referencing the transfer from e000111 and submitting a regulatory activity.

0003 0004 Sponsors F and P undertake business as usual

Product C Product D

0005 Sponsor Y submits first sequence as 0005 referencing e000222

0004 0005 0006 Sponsors F, P and Y undertake business as usual

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Change of sponsor – what to do (II) Sequence type: Change of Sponsor Sequence description: Initial

• Module 1.2.4 Change of sponsor – a copy of the form Notification: Transfer of Sponsorship following transfer/assignment of business or

interest in therapeutic goods – a letter from the original sponsor confirming access to all previously submitted data OR the original

sponsor and the new sponsor must complete the Co-marketed medicines declarations (Module 1.5.5). • Module 1.3.1.1 Product information – clean • Module 1.3.1.2 Product information – annotated • Module 1.3.1.3 Package insert • Module 1.3.2.1:Consumer medicines information – clean • Module 1.3.2.1:Consumer medicines information – annotated • Module 1.3.3 Label mock-ups and specimens • Module 1.6.3 Letters of access (from DMF, PMF and CEP holders)

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Cross referencing • <m1-4-3-clinical>

<leaf ID="N3774598bcdd74d5891d954542c552eee" operation="new" xlink:href= "../../../../e000111/0000/m1/au/104-expert/1043-clinical/dr-a-jones.pdf" checksum=

"b6ba67a7740d12bcb938f2850baa584e" checksum-type="MD5"> <title>Expert Dr. A. Jones</title> </leaf> <leaf ID="N3ad8bf59e3fd4cb5bbd4f82b31350887" operation="new" xlink:href= "104-expert/1043-clinical/dr-b-schmidt.pdf" checksum="bf30251122458c7c5c17dc3ed0002c1e" checksum-type="MD5"> <title>Expert Dr. B. Schmidt</title> </leaf> <leaf ID="Ne0eeb59ae2f74ba5832965154db4cc13" operation="new" xlink:href= "104-expert/1043-clinical/dr-c-smith.pdf" checksum="f1e209870c05f15eef24f4b2e1e74a0f" checksum-type="MD5"> <title>Expert Dr. C. Smith</title> </leaf>

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Pre-Advisory Committee response (I) A3 Pre-ACPM covering letter eCTD A3a Sponsor’s comment on evaluations (remaining

issues). Module 1.0.3 Response to request for information

A3b International regulatory history Module 1.11.1 Foreign regulatory status A3c Adverse reactions update Module 1.0.3 Response to request for information A3d Sponsor’s comments on PI Module 1.0.3 Response to request for information A3e Sponsor’s comments on foreign PI Module 1.0.3 Response to request for information A3f PSUR Module 5.3.6 Reports of Post-Marketing Experience A3g, A3h etc Other documents Module 1.0.3 Response to request for information C1 PI (annotated and non-annotated) Module 1.3.1.1 Product information - clean

Module 1.3.1.2 Product information – annotated C1a CMI (annotated and non-annotated) Module 1.3.2.1 Consumer medicines information – clean

Module 1.3.2.2 Consumer medicines information - annotated C2 European SmPC (including UK or Swiss) Module 1.11.2 Foreign product information C2a US Prescribing Information Module 1.11.2 Foreign product information C2b Canadian Monograph Module 1.11.2 Foreign product information C2c New Zealand Product Information Module 1.11.2 Foreign product information

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Pre-Advisory Committee response (II) Sequence type: A - NCE New Chemical Entity Sequence description: Pre-Advisory Committee response Sequence elements: Module 1.0.1 Cover letter Module 1.0.2 Lifecycle management tracking table Module 1.0.3 Response to request for information Module 1.3.1 Product information Module 1.3.2 Consumer medicines information Module 1.11.1 Foreign regulatory status Module 1.11.2 Foreign product information Module 5.3.6 Reports of Post-Marketing Experience

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Submission is rejected or withdrawn (I) • If a complete submission is withdrawn or rejected,

– You should submit a consolidation sequence to remove the scientific and regulatory content from the current view.

Example: Sequence type = A - NCE New Chemical Entity Sequence description = Withdrawal

• Not all of the content submitted in the rejected or withdrawn submission should be removed :

– Certain administrative, scientific or regulatory information may be used in future submissions (e.g. a clinical study report for a rejected new indication will still contribute data about clinical safety in future submissions)

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Submission is rejected or withdrawn (II) • Module 1

– The original cover letter, lifecycle management tracking table and application form should not be removed from the current view.

– All other documents should be removed. – Particular care should be taken to remove from the current view the versions of any labelling documents

associated with the rejected or withdrawn regulatory activity. • Module 2

– All summary documents should be removed from the current view. • Module 3

– All content files associated with the rejected or withdrawn regulatory activity should be removed from the current view so that only the previously approved/submitted content remains in the current view.

• Modules 4 and 5 – Content should not be removed from the current view unless the TGA specifically requests you to do so.

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Submission is rejected or withdrawn (III) • Removal of documents associated with a rejected or withdrawn regulatory activity may be achieved in the

following manner: – Any leafs (associated only with the rejected or withdrawn regulatory activity) where content was submitted

for the first time in this section, should be updated with a “delete” operation leaf.

– Any leafs (associated only with the rejected or withdrawn regulatory activity) where content was submitted for a second or subsequent time in this section, should be updated with a “replace” operation leaf that points the content back to the version of the leaf used prior to the submission of the rejected or withdrawn regulatory activity.

– Any leafs (associated with the rejected or withdrawn regulatory activity) but with content also shared with other approved regulatory activities should be updated with a “replace” operation leaf that points to a new content file that contains only the approved content.

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Questions?

Please email any questions to esubmissions@tga.gov.au

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