If you visit the EMEA eSubmission: What’s new page, you will see that several new documents have been posted (date says July 27th, but I think it was really after that…).

The updated documents are:

• Updated EU Telematics EU eCTD Change Request/Q&A Tracking Table
• EU Validation Criteria v2.0
• EA Practical/Technical Q&A on eCTD Submission V0.4

These updates are mainly in support of the recent EU Updated M1 v1.3 (see my previous post on this topic). There are about 10 new change requests (see those starting with CR-20080415) and one new Q&A (22, not yet answered).

Validation criteria changes are minor and are described at the end of this Excel document in a table. I’ve reproduced them here, with my comments in square brackets:

1. Criterion #37 deleted (see EU CR Q&A Tracking Table CR-20080610) [this was a DPI check that turned out to not be technically feasible with the valdidation tool being used.]

2. Reference of criterion #44 changed from EU Q&A 13 to ICH Q&A 36 (see EU CR Q&A Tracking Table CR-20080610-01 [although this is described as a "change" this is in fact a new criterion, stating "There are no unreferenced files in M1, M2, M3, M4 & M5 folders (including subfolders but excluding ‘util’ subfolders)" and having a priority of A, Serious".]

3. Criterion #18 changed to indicate that a title must exist with a delete operation - (see EU CR Q&A Tracking Table CR-20080610-02) [the critieria was changed from saying a title is not required for a file that has an operator of delete to saying that it is required.]

In addition to the usual minor updates and fixes, I identified the following more significant changes from version 0.3. [By the way, it's not an easy process to compare these documents! PDF comparision results are difficult to use and I had to go through a number of cumbersome steps to convert to Word and compare. It would be nice if EMEA included more detailed info in their change log...]

FILE FORMATS Q2

The answer to Q2 has been enhanced with the bolded information and the example corrected as shown below.

Q2. As the EMEA requires the submission of RTF/Word documents for the Product Information (SPC, Labelling and Package Leaflet) and for some Module 2 documents, in addition to PDF, how should these Word documents be handled?

All Product Information Word/RTF files submitted to the EMEA (outside the eCTD backbone and therefore it not necessary to observe eCTD file naming conventions) should be named using the following convention, including the full application number/procedure application numberonly if this is known at the time of submission:

ProductName-H-ApplicationNumber-ProcedureType-ProcedureNumber-PI-languagecode

Example: WonderPil-H-640-S-15-PI-en

Note the correction here - the previous document had a reference to a “product number”. Strangely, this example is repeated later in the document (see FILE NAMING Q1) but was not corrected there.

SUBMISSION MEDIA Q2

 EMEA clarified the answer to Q2 by adding the note appearing in bold text below:
Q2. Must hard media be used for the submission of eCTD i.e. can secure email (Eudralink) be used?

Hard media (e.g. CD, DVD) must be used for the submission of all eCTDs. Eudralink can be used for eCTD in addition to hard media, but not as the sole medium for submission.

Please note that this requirement for hard media applies to EMEA as an agency, and may not be reflected in all National Competent Authorities involved in the Centralised Procedure – individual guidance from NCAs should be sought if necessary.

eCTD and PIM Q2

 EMEA clarified when PIM may not need to be submitted within an eCTD:

Q2. If PIM is submitted with an eCTD submission, how should this be done?

It is expected that PIM submissions will be more numerous than eCTD submissions during a typical procedure, since PIM is a two-way exchange mechanism designed to support the management of the product information, the part of the dossier subject to the most change and rapid amendment during any procedure. Therefore, there will be some PIM submissions made without an accompanying eCTD via Eudralink. However, it is expected that, when a major lifecycle eCTD submission is provided as specified
in the response to Q1 under ‘Submission Milestones’ in this document, then the latest PIM submission will be included within the eCTD submission, if applicable, to ensure alignment. (The PIM submission does not have to be included within the eCTD submission at such points, however, and can be submitted as a separate PIM submission even if submitted simultaneously with the eCTD, as is detailed in the PIM specification).

SUBMISSION MILESTONES Q1

 EMEA provided clarification about when labeling translations are needed:
Q1. When, in a procedure, at a minimum, does EMEA expect an eCTD submission to be provided?

Updates to key milestones

1. Initial submission (Day 0 of procedure)
2. Response to business validation issues (if required)
3. Response to List of Questions (i.e. Day 121 for a new application)
4. Response to List of Outstanding Issues (i.e. Day 181, if required)
5. Application as agreed at Opinion (inc. agreed EN product information if changed at CHMP)
6. Provision of translations (i.e. Day 215 for a new application)*
7. Provision of final agreed updated translations following linguistic review (it is not also required to send interim working versions of the product information before this point as eCTD) **
8. Decision (i.e. final amended documentation if any changes occur during the Standing Committee phase)

** Note also that it is not required that interim working versions of the product information documents exchanged during the linguistic review phase are followed up by an eCTD containing PDFs, or on hard media – only the original and final agreed translations should be submitted in this manner.

CONVERSION OF EXISTING APPLICATIONS TO eCTD Q1

 A clarification was added about submission of reformatted documentation:

The submission of reformatted documentation (commonly referred to as a ‘baseline’ submission, although the corresponding eCTD DTD submission type value for such a submission with re-formatted information is ‘reformat’) should preferably occur simultaneously (but separately) with the submission of a variation, line-extension or renewal.

Europe recently made some fairly significant changes to eCTD Module 1 Guidance. You can see and download the specification, release notes, examples, and overall package at: http://esubmission.emea.europa.eu/eumodule1/. Look for an update from your publishing vendor as DTD and publishing tool changes are needed to support the new spec - and remember that EMEA has said that they require compliance by the end of 2008, so plan now for system updates and any validation impact they may have.

The following changes were determined by comparing the new EU Module 1 Specification Version 1.3 (May 2008) against the previous approved version 1.2.1 (October 2006).

Changes to Main Body

• Acceptability of XML for cover letter, variation form and renewal form.
  Inability to accept digital signatures.
• Instruction not to use placeholders for content sections that are absent, but to discuss in summary documents instead.
• Confirmation that files in M1 can be referred to in index.xml and files in M2-M5 can be referred to in eu-regional.xml.
• Additional guidance on the envelope, covering the “eu-envelope” values of “emea“, “common” and specific member state values. (See the section Envelope.)
• Additional guidance on directory structure. The recommended directory structure for the use of country and language identifiers is described in Appendix 2. In general, Modules 1.0, 1.2, 1.3.2, 1.3.3, 1.3.4, 1.3.5, ‘Additional Data’ and ‘Responses’ have country subdirectories. Module 1.3.1 (Product Information) has both country and language subdirectories. (see the section Directory / File Structure.)
• Additional guidance on node extensions (finally). Discusses use, placement and nesting. (See the section Node Extensions.)

Changes to Appendix 1: Envelope Element Description
Changes to agency element – has been changed from agency-name, mandatory, repeatable to an agency parent element and code, with the code mandatory and unique.

• Addition of new submission types (metadata valid values).
• Removal of the Country element under Related Sequence.
• Updates to guidance and examples around Related Sequences.
• Changes to Appendix 2: Directory / File Structure for Module 1
• Note that the operation attribute for the eu.regional.xml should always be set to ‘new’.
• Instructions on the placement of a “tracking table” (this is within the context of the Cover Letter). (See “MRP/DCP Tracking Table Description”, Version 0.1, May 2008.)
• Additional/clarified guidance on naming of labels for one language or multiple languages.
• Addition of element for 1.10 Information relating to Paediatrics.
• Instruction that “Additional Data” should only be used for information required for National, MR and Decentralised Procedures and not being applicable for the Centralised Procedure.
• Recommendation against the use of custom stylesheets.

Changes to Appendix 2.1: Destination Codes

• New destination (country) code Common
• Removed * stating that Bulgarian and Romanian languages should not be used before those countries join the EU.

What Does It Mean?

Some of these changes will be taken care of by your eCTD tool or in how it is used by your publishers. Others may require changes in your processes

• If you have been using placeholder documents, you will need to update your process to discuss “missing” documents in summaries (this is not really new - the authorities have been stating this position in meetings and presentations for some time)
• You may want to review your use of node extensions in organizing your clinical study documents
• You will need to introduce the “tracking table” for MRP/DCP
• Ensure that you are not using the “Additional Data” section for the Centralised procedure
• Review your use of metadata since new values and changes have been introduced
• Ensure that your procedures are in place for creating, reviewing and approving documents 1.10 Information relating to Paediatrics.

With the recent clarifications to the use of the Related Sequence in both US and EU, now is also a good time to make sure your team understands how to use this critical piece of metadata.