The ICH guidance is basically silent on this subject, although the structure does not specifically prohibit any valid relative link. EMEA has stated that it is not allowed - in “EU Region Question and Answer and Specification Change Request Document”, see question 13:
“In the EU it is possible to refer to a file located in the same sequence or any previous sequence of the same eCTD. It is not possible to refer to other eCTDs.”
If you think about it a little, it requires each agency to maintain a specific set of folders in order for the links to work, and for the sponsor to understand what that structure is.
For example, if the agency stores eCTDs in a known folder path like this:
Gary Gensinger of FDA has said in several presentations that FDA will accept references to documents in other applications.
In order to do this, your publishing tool must be able to handle this scenario. A leaf must exist in your new application (you cannot reference leafs from other applications, only content files). You will need to know:
Access in through the hlink:xref element, and the operation attribute is NEW.
Gary provided the following example:
With the following commentary:
You want to reference a leaf submitted in 0000 of your IND 012345 for NDA282166, sequence 0000 - Your file is named study-report.pdf in 188.8.131.52. Using the following relative path will allow you to reference the study report:
../ gets you out of the 0000 submission in NDA 282166
Adding ../ gets you out of the NDA 282166
Adding IND012345/0000/m5/5352 gets you to your files location
What I haven’t heard is how many people are taking FDA up on this offer.
By the way, the RPS specification will be designed to allow cross application referencing from the start, and will not reply on a relative folder path.
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:
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...]
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:
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.
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.
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).
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
** 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.
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
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.
Changes to Appendix 2.1: Destination Codes
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
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.
In addition to updates and correction of references, the main changes in the Notice to Applicants are:
Application forms were also re-issued - see http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol2_en.htm#2b.
Next posting will examine related changes to the EU M1 specification.
EMEA and PMDA provided an update on eCTD status at the traditional “Update on Regulatory Authority Experience” session.
Tim Buxton was the speaker from EMEA. He provided the following statistics on eCTDs received between July and December 2007:
Tim also mentioned that seven EU authorities already accept eCTD only without paper.
Next, Tim discussed the new EU M1 guidance, which incorporates 24 change requests. Tim stressed that this guidance is mandatory by December 31, 2008, and that this is a hard deadline because the most significant change, which is related to pediatric information, is needed immediately (in the short term, put this in the “Other” slot in M1). He also mentioned that the new tracking table for MRP/DCP goes into the same slot as the cover letter.
To access the new M1 specification, see http://esubmission.emea.europa.eu/eumodule1/docs/EU%20M1%201.2.1/EU%20%20M1%201.3/EU%20M1%20Specification%20v1.3%20FINAL%20.zip
To access the underlying CTD Guidance “Volume 2B Notice to Applicants: Medicinal products for human use: Presentation and format of the dossier: Common Technical Document (CTD), see http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/update_200805/ctd_05-2008.pdf
Tim discussed the (relatively) new XML application. The EMEA has been disappointed that sponsors are not using it more extensively, and would like to encourage sponsors to begin using it as soon as practical.
Tim was asked about the intention of developing a submission gateway. The EMEA already has a gateway for ISCRs, similar to the FDA’s. They plan on developing a gateway for eCTD, but are not able to announce a date at this point.
Yasuhiro Araki spoke next, representing PMDA. He presented the eCTD review process in detail. PMDA is ready and able to accept eCTDs and has developed tools and processes in support of eCTD, but as of May 2008 has received only 9 original applications (17 sequences) and 71 reference applications (100 sequences). Reference applications are essentially review aids with paper being the official copy.
Japan still needs paper for M1 and M2 - the main reason for thisis the use of external experts in the review process.
EMEA has reinforced its position on implementing the electronic-only submission of information in support of marketing authorisation applications in the centralised procedure, and, ultimately, implementation of the Electronic Common Technical Document (eCTD) as the required format for electronic submissions, in two new documents dated 22 January 2008:
Some key points in the Statement of Intent and accompanying Q&A include:
Key provisions include the establishment of a central repository and a single review tool for eCTDs submitted using the centralised procedure, which are necessary steps to eliminate the need for hard copies.
The EMEA gave some recommendations on implementing eCTD in the EU, and also has promised a further Q&A document on practical and technical aspects of eCTD implementation in the centralised procedure. During the February 7th International Regulatory Update session at the DIA Doc Management conference, Tim Buxton of the EMEA stated that this guidance will include the detailed process for submitting eCTD to the EMEA and will also discuss digital signatures.
Another key point stated by the EMEA is “The vendor market in eCTD builder tools and consultancy on all aspects of eCTD preparation and submission is mature, and companies should research these options, if applicable, for engaging external expertise. The EMEA is unable to list or recommend specific vendors. However, companies interested in gaining more information relating to software should contact pharmaceutical trade associations active in the EU for details of existing eCTD Topic Groups.”
The planning horizon for full electronic-only implemention is now approaching the minimum time in which eCTD readiness can be fully achieved. It’s time for sponsors doing business in Europe to become fully prepared if they are not eCTD-ready right now.