A significant new guidance document, Guidance for Industry on Providing Regulatory Information in Electronic Format: eCTD electronic Submissions, has been posted on the EMEA eSubmissions website. 

This document has been prepared by the eCTD Guidance Topic Group of the TIGes. It is largely based on Guidance for Industry on Providing Regulatory Information in Electronic Format: Non-eCTD electronic Submissions (NeeS) Version 1.4, and also reproduces a significant amount of information from “QUESTIONS AND ANSWERS RELATING TO PRACTICAL AND TECHNICAL ASPECTS OF THE IMPLEMENTATION”, hereafter referred to as “Q&A”.  However, it also provides a fair amount of new guidance and that’s what I’ll be focusing on in this post. 

It’s important to note that this is not a final document – it’s a “Draft for Testing”. The Topic Group anticipates comments from NCAs and applicants which will enable future versions to reflect practical experience of users. In this way the document will evolve to become an essential work of reference in this area.  They did not describe a specific mechanism for obtaining these comments.  National Competent Authorities have been strongly recommended to adopt this guidance as the basis for their dealings with applicants. 

The document includes a shout-out to RPS, for those of you wondering if Europe will really move in that direction. “International standards development through ICH, ISO and HL7 will eventually lead to the eCTD becoming part of a wider group of regulated product submissions, covering medical devices, veterinary products and food additives as well as medicinal products.” 

Unfortunately, it is not bookmarked (I took a few minutes to create my own bookmarked copy as I anticipate using it a lot.)  There are a also number of references to NTA that I find puzzling.  For example, the applicant is referred to Volume 2B for the following “subfolders should be used to organise the files for each module in a submission: m1, m2, m3, m4, and m5 following the principles set out for the CTD in Notice to Applicants, Volume 2B” – but 2B never mentions folders.  Volume 2A Chapter 7 is a reference for file formats, but again that is not discussed in the current Volume 2A.  Possibly a re-issue of these documents is in the works? 

New Guidance 

Cover Letter. The cover letter guidance does not repeat the information that was in “Q&A”.  Instead it states “The cover letter should, at least for MRP and DCP applications, include as a minimum, the information specified in the CMDh Guidance document” and also mentions that there is a template that can be used.  The NeeS guidance document included a link to a cover letter template, but this link (which was on http://www.hma.eu/) is now broken.  If anyone knows the location of the cover letter template (for NeeS or eCTD) please post a response on the blog!  The guidance also states that the cover letter should mention if the product information is being provided as PIM data.  Finally, good naming practices for forms and cover letters are discussed. 

Sequence Numbers: clarification was provided that if possible the initial sequence number should be 0000, even if the first sequence is not an initial MA application (if there is a good reason for deviating, it should be explained in the cover letter).  Sequences numbers should normally follow the order of submission but EMEA and most NCAs are able to accept and view sequences submitted out of numerical order. A Sequence Tracking Table should always be included as an annex to the cover letter in every submission within MRP/DCP. A similar tracking table is recommended for national applications. 

Placement of word documents.   EMEA has already said that these files should not be added as leaf elements within the eCTD structure, but never before stated where the physical files should be placed.  In this guidance, they state “They should be provided in a separate folder called, e.g.“<sequence>-working documents” on the CD/DVD containing the eCTD. 

Explicit forbidding of cross-application references.  Although I believe EMEA has stated this in presentations before, they explicitly state “Currently it is outside the scope of current eCTD specifications to allow cross references to documents, sections or modules in other eCTD dossiers.” 

Additional Guidance on Product Names.  Some guidance is included in the M1 V1.3 specification.  Additional details include:

• ATC If unknown at the time of submission, the entry can say ‘to be confirmed’.
• Invented-name The trade name/invented name for the medicinal product covered by the application. If the eCTD covers multiple strengths or dosage forms, this entry does not need to describe the complete name, a simple entry, for example, ‘Wonderdrug’ will suffice.

Use of Response Documents section.  This section is worth quoting verbatim, as it gives new guidance on use of node extensions, folder structure, etc. 

To help in the management of responses over the lifecycle of the eCTD, the responses relating to a particular regulatory activity should be grouped under a node-extension in the eu-regional.xml file. The title of the node-extension should identify the regulatory activity (e.g. Responses to Questions for the Initial Application, Responses to Questions for Type II Variation 028, etc.). It is recommended that you provide a full copy of the list of questions received from the agencies as the first leaf in this section. 

It is recommended that the responses be split up into separate files for each major section of the submission (e.g. Quality, Non-clinical and Clinical). You should use the leaf title to identify the particular set of responses (e.g. Response to Major Objections - Quality). If responses to more than one question are submitted in a single file then you should use bookmarks within the PDF file to clearly identify each response. It is possible to submit the response to each question in a separate file but if you choose to do so then you must use node-extensions and leaf titles to group and identify the responses under the top level node-extension. 

All of the files for the response documents should be placed in the folder m1/eu/responses/CC, where CC is the appropriate country identifier code for use in MRP/DCP. 

Use of the additional data section.  Previously stated guidance is repeated – that is, this is not used in the Centralised procedure – but a comment mentions that this section can be used for all procedures when an old version of a DTD is being used during an agreed transition period, to support inclusion of a newly defined section of Notice to Applicants.

Organization of the dossier. Annex 3 discusses advantages and disadvantages of eCTD application structures, including one combined eCTD for multiple strengths and dosage forms, or one eCTD application per strength or dosage form.

Organization of Module 3.  An entire annex addresses best practices in the structure of Module 3.  This annex discusses

• Recommendations around the choices of attribute names (drug product, substance, manufacturer, dosage form, etc.)
• Approaches for handling manufacturers (separate for each manufacturer, single section for all, or a possible hybrid)
• Approaches for handling strengths (separate for each strength, single section for all, or a possible hybrid)
• Excipient issues, including handling of compendia excipients (a single file that addresses CTD topics 3.2.P.4.1 to 3.2.P.4.4 for all excipients can be provided), naming conventions, etc.

Modular Nonclinical Study Reports.  The guidance sates that granular reports created for the US can be submitted without re-organization in Europe. 

Organization of Clinical Studies.  For the first time, a recommendation is given to use node extensions for all reports, even those containing only one document. If case report forms and individual patient data listings are submitted, they should be placed in the same order as the clinical study reports appearing in m535 and should be indexed by study. Note that bookmarks will not be required as there will be no further internal structure.  Study synopses can be provided either as copies in 2.7.6 or as hyperlinks to synopses in Module 5.

Withdrawal of an application.  Instructions are given for withdrawal of an entire product or a specific dosage form or strength.

Guidance on Text Searchable Documents. For the first time, this guidance is given for eCTD in Europe.  It is identical to the guidance given for NeeS.