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eCTD workshops: Question and answer sessions

13 January 2015

On 10 December in Sydney, and 16 December in Melbourne, the TGA and ARCS hosted two workshops on the implementation of eCTD, eSubmissions in Australia. The following is a summary of the question and answers sessions given at the workshops.

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Presubmission and submission issues

The pre-submission phase is not part of the eCTD pilot. There are no changes to the pre-submission process and sponsors should continue to submit the Pre-submission Planning Form according to the current registration process requirements.

Dossier format

The experience gained handling and evaluating eCTD applications will be reviewed in February 2015.

Applicants currently have the option of eCTD or NeeS. If an applicant opts to use the eCTD then all future submissions relating to that product must be in the eCTD format.

Harmonised guidelines, specifications and forms for electronic applications are currently being drafted by the TGA.

Whilst the eCTD format is not mandatory in Australia, TGA notes that other jurisdictions are very advanced in their implementations of eCTD and industry should prepare for eCTD submissions.

A time frame for phasing out paper copies is yet to be decided.

A time frame for such a transition period has not been determined.

Sponsors may apply to be part of the eCTD pilot at any time. A sponsor will need to consider that aspects of Module 1 differ in eCTD and NeeS applications and a paper dossier is required for NeeS applications. A sponsor needs to ensure they have adequate time to appropriately format Module 1 and print a paper copy of the dossier if their request to participate in the pilot is not accepted.

TGA will continue to accept dossiers in eCTD format once the pilot phase has ended and is an accepted format for prescription medicines dossiers.

The TGA will accept baseline eCTD dossiers containing information previously submitted to the TGA. Baseline dossiers should not contain information that has not previously been submitted to the TGA either in paper or electronic form. TGA will not re-evaluate or impose a fee for the submission of data in a baseline submission.

Validation issues

TGA will validate NeeS applications. The validation criteria for NeeS applications are on the TGA website. Lorenz have published a validation tool for Australian NeeS application. As other vendors incorporate the TGA specifications and notify the TGA, we will publish details on the TGA website.

During the pilot phase sponsors include a validation report with their application and will be aware of any validation issues prior to submitting the application to TGA.TGA will assess the extent and nature of any errors before deciding whether to request the errors be corrected and the dossier re-submitted.

Requests for assistance should be submitted via email to esubmisisons@tga.gov.au. TGA will consider NeeS dossiers that do not pass NeeS validation criteria on a case by case basis.

Validation criteria are graded as either a 'warning' or an 'error'. eCTD sequences that fail to meet one or more of the criteria graded as 'error' may be returned to the sponsor for fixing and resubmission.

No differences have been seen or would be expected. TGA would not know whether an eCTD application in Australia had been derived from an eCTD application for the FDA or one for the EMA.

No.

Sponsors should validate the eCTD dossier and include the validation report in the application prior to writing the application to appropriate media.

Category 3 and minor variation application issues

TGA will develop guidelines for handling data associated with a self-assessable change. If the TGA requests the data to be submitted, then it should be another sequence in the format of the application (NeeS or eCTD).

The requirements for paper and electronic dossiers will be the same across all prescription medicine application types.

Category 3 applications associated with a previous eCTD dossier must be in eCTD format and a baseline submission will not be required.

A baseline submission is encouraged for those Category 3 applications involving a switch to eCTD, i.e. previous applications were in the paper or NeeS format; however, it will not be mandatory to provide a baseline submission.

The eCTD format will be an option for all prescription medicine application types.

Guidelines to enable the submission of Category 3 applications in the eCTD format are being prepared. Once a sponsor has chosen the eCTD format for a product, all future submissions must be in the eCTD format.

Specific documents and eCTD

PSURs may be submitted as an eCTD sequence. If the PSUR was associated with a previous eCTD application it must be submitted as a new eCTD sequence for that application.

Post-approval documents should be submitted as a new sequence to the associated eCTD application.

Applicants should include the following information in Module 3.2.R, where appropriate:

  • Process validation scheme for the drug product
  • Certificates of suitability (including any annexes)
  • Information relating to Transmissible Spongiform Encephalopathy (TSE)
  • Certified product details
  • Supplier's declarations regarding compliance with packaging standards and colouring standards.

It is not clear which document in Module 1 could contain the links - it would be an inappropriate use of the Cover letter. It is also not clear where these documents would reside in other parts of Module 3.

Approval letters for prescription medicines are provided electronically and in the form of an original, signed paper copy. We are working towards communication being primarily via electronic means.

The components of the pre-ACPM response will be mapped to the appropriate Module 1 sections for those applications submitted in the eCTD format, for example, Australian Product Information (PI) to Module 1.3.1; Overseas status to Module 1.11.1 Foreign regulatory status.

The full suite of updated TGA guidances is being revised to emphasise processes around eCTD and electronic submission. During the pilot, applicants initially should include a cover letter assuming no validation issues. If the submission then fails validation, and the applicant feels they are attributable to a deficiency in the specifications or their interpretation, then the issues should be detailed in the cover letter and the submission published and written to media for submission to the TGA. The TGA will determine if it can then accept the submission.

As with the cover letter, the 'note to the reviewer' should not include information intended to be evaluated. It would be used for providing further information to facilitate navigation (e.g. on hyperlinking or navigation).

Yes. A table of contents, or equivalent document, that provides TGA with comprehensive information on the scope and extent/size of the dossier will continue to be required to allow TGA to plan an appropriate evaluator and time frame for the evaluation.

For applications using the eCTD format, the index.xml and au-regional backbones, as viewed using style sheets and converted to PDF, may be used to create a Table of Contents.

Current guidance requires that a full list of literature references is provided.

TGA acknowledges that it will not be appropriate for all draft documents to be submitted in the eCTD format. In general, documents that contain substantial material changes will be expected to be submitted as an eCTD sequence. TGA expects to develop guidance around this issue and to include examples of the types of changes that would and would not constitute a new eCTD sequence.

Forms are being updated to be consistent with eCTD functionality.

TGA's strong preference is to 'replace' a file rather than submit an 'addenda'.

Some eCTD tools have the capacity to count the number of pages in an application or in a section of an application. If so please include this information. If you eCTD tool does not have this functionality, please leave blank.

eCTD baseline dossiers

For baseline dossiers involving a major variation, such as an extension of indication, does TGA prefer that sponsors submit all of the available data for that product or just the data applicable to the extension of indications application?

A baseline submission is a compilation of the current status of the dossier, i.e. resubmission of currently valid documents that have already been provided to an agency but in another format. The sections provided to make up a baseline can be defined by the applicant, but any omissions should not render the submitted content misleading.

It is highly recommended but not mandatory to use a baseline as a start of an eCTD when changing from paper or NeeS and to provide as much content as possible in the eCTD. The baseline would preferably consist of high quality electronic source documents, but good quality scanned images would also be acceptable in these cases, preferably with Optical Character Recognition (OCR) to facilitate text searching.

It should be clearly stated in the cover letter of the 'baseline eCTD sequence' that:

  • the content of the previously submitted dossier has not been changed, only the format
  • all the studies have previously been submitted to TGA; and
  • any omissions do not render the submitted content misleading.

The TGA will not convert new or existing submissions to eCTD format. The TGA wishes to avail itself of the features of the eCTD format to ensure integrity of submissions and improve the quality of submissions. We will only accept validated eCTD submissions published by applicants.

Baseline submissions should be as complete as possible to maximise the benefits of the eCTD format including ongoing lifecycle management. If submitting a baseline in anticipation of a variation then it would seem appropriate to include all relevant studies relating to the registration of the product and include the additional studies relating to the variation as another sequence. To assist transition, the TGA will consider accepting partial baseline submissions.

Other regulators have started eCTD format submissions with New Chemical Entities. The TGA recognises that there are advantages to using the eCTD format for existing products but needs to undertake further work in this area including guidance for industry.

The preferred approach is for the NeeS dossier to be converted to an eCTD prior to the commencement of a regulatory activity. If converting to eCTD format during a regulatory activity and only the initial sequence of that activity had been submitted, the original application should be resubmitted as a baseline submission (sequence 0000) and the s31 response could then be submitted as the first sequence of this dossier.

Multiple trade names and sponsorship transfer issues

If all products within an application are transferred, the name of the sponsor will change in the envelope and relevant files will need to be submitted e.g. new PI, new CMI, labels etc.

If a subset of products within an application change sponsorship, a new eSubmission Identifier will be created for the new sponsor and this will be linked back to the previously submitted data by reference to the previous esubmission identifier in the cover letter. New sequences will need to be submitted under each eSubmission Identifier for future submissions.

Miscellaneous

Module 1 was re-organised to provide a structure that was suitable for both prescription and OTC medicines.

In the future TGA will establish a portal (or electronic submission gateway) for sponsors to submit eCTD dossiers. Currently prescription medicine applications should be submitted on a disc, USB media or external hard drive.

TGA may review response times if eCTD dossier requirements have been shown to impact upon the time to prepare a response.

DMFs will be appropriately referenced in the envelope.

Navigation through an electronic submission is greatly enhanced by the appropriate use of bookmarks and hypertext links. ICH Q&A number 53 states:

  • It is expected that any document that has a Table of Contents (TOC) will have bookmarks (see the eCTD specification for details). Documents without TOCs should have bookmarks included where it aids in the navigation around the document content. For example, a 4 page document summarising findings could require bookmarks to aid navigation. However, a 300 page file containing a single data listing might not require bookmarks as there is no further internal structure.

In general terms, bookmarks and hyperlinks should be used to aid navigation; however, the overuse of hyperlinks may confuse rather than help assessors. Overuse may also cause problems later in lifecycle management.

Additional details on creating bookmarks and hypertext links in PDF documents can be found in the ICH eCTD Specification Appendix 7.

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Study reports should usually be submitted as multiple documents (a synopsis, a main body of the study report and appropriate appendices). Appendices should be organized in accordance with the ICH E3 guideline, which describes the content and format of the clinical study report.

In choosing the level of granularity for reports the applicant should consider that, when relevant information is changed at any point in the product's lifecycle, replacements of complete documents/files should be provided. (see ICH Granularity Document).

Node extensions may be used where additional navigation in the XML backbone is required. A node extension for each study may be useful to group together the multiple leaves that make up the study and its modular appendices. Also, it could be useful to differentiate reports associated with a different dosing regimen for the same indication.

See Granularity Document (Annex to ICH Topic M 4 Common Technical Document for the Registration of Pharmaceuticals for Human Use –Organisation CTD. (CPMP/ICH/2887/99)

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