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Archive for the ‘EMEA’ Category

New EMEA M1 Spec (V1.4) in August; Other Agency News

posted by mr.erhabi511 @ 9:36 PM
Thursday, July 16, 2009

EMEA has announced that they will be releasing a new M1 eCTD specification in early August.  EMEA will be releasing version 1.4, including a new DTD, implementation guide, transition guide, and validation guide.  According to Claire Holmes of EMEA, this new version will accommodate recent updates to guidance on variations.

The new version will be recommended from January 2010, and mandatory from February 2010.

Gary Gensinger of the FDA has also confirmed that a new US module 1 specification is in the works, with no target date announced yet.

As I reported earlier in the week, SwissMedic has released their draft eCTD M1 specification and validation criteria.  Stephan Jaermann of SwissMedic has stated that additional documentation – Guidance for Industry and Q&A – will follow soon.  The SwissMedic pilot program will continue through October, with implementation to follow.  Initially, only MAAs will be accepted, with Variations accepted in a future phase.  SwissMedic will still accept paper submissions for the foreseeable future, but all electronic submissions must be in eCTD format (no NeeS).

Addendum: SwissMedic has as of July 17 published Guidance for Industry on Providing Regulatory Information in eCTD Format and Questions and Answers of Swissmedic eCTD Implementation.

SwissMedic has issued a package of eCTD related specifications 

·        Swiss M1 Specification for eCTD

·         Other Documents (DTD/MOD)

·         Swiss eCTD Validation Criteria  

I have only done a cursory analysis as my day job is a bit overwhelming at the moment.  The specification differs notably from the EMEA spec in several areas:

·         SwissMedic has issued their own file and folder naming conventions for M1 as of course their M1 contents differ from EMEA

·         Module 1 metadata is different, and includes a SwissMedic number and the galenic (dosage) form in both English and other languages, and does not include ATC or procedure type

·         The DTD appears to allow M1 to be repeated per galenic form

·         The concept of regulatory activity, as implemented in related sequence, is present.  However, the concept of first and second level activities is not present as it is in EU/US.  For example, a sequence of type na-nas can relate to another sequence of type na-nas.

·         The leaf element includes some new attributes such as actuate-list and show-list, and gives a list of values.  However, these are not explained or even mentioned in the guidance document.

In other news, EMEA issued their guideline for e-submission for a veterinary medicinal product  The guideline specifies the basic parameters required for an acceptable electronic submission, and includes a specification for the folder structure (the granularity) to be used in a basic electronic submission to be known as VNeeS.  It does not mention eCTD.

Warning: Some HAs not accepting PDFs other than 1.4

posted by mr.erhabi511 @ 2:19 AM
Thursday, June 4, 2009

Recently, some sponsors have been reporting the rejection of eCTD sequences or NeeS containing PDFs of any version other than 1.4.

The Swedish agency Medical Products Agency (MPA) states on their website on the page Electronic submissions to the MPAThe MPA will check eCTDs against the A criteria listed in the “EU eCTD Validation Criteria” v.2.0 (see link to the right), and also check for the B criteria that the eCTD has PDF files in format PDF 1.4 only (very important for archiving).”  Some sponsors have reported that MPA is actually rejecting eSubmissions containing PDFs other than version 1.4, even though (as noted) this is only a “B” error in Europe (see Error 37 in EU eCTD Validation Criteria V2.1).  The definition of “B” Priority is “accept but may request corrections (fix with a subsequent sequence)”.

The French authority Agence Française de Sécurité Sanitaire des Produits de Santé has also been reported to be refusing submissions containing PDFs other than 1.4, but I could not find anything on their web site to support this except a mention in NOTICE TO APPLICANTS FOR MARKETING AUTHORISATIONS FOR MEDICINAL PRODUCTS FOR HUMAN USE  as follows: “The file format for text documents must be PDF 1.4″.

ICH’s guidance on this (in the eCTD 3.2.2 specs) is “All ICH Regional Health Authorities are able to read and have agreed to accept PDF files saved as PDF version 1.4… Please consult regional guidance to submit other versions of PDF.”  FDA of course has a whole document on this topic, Portable Document Format Specifications (note the new location on their re-organized web site).  I have heard FDA say in the past that their issue with PDF formats is also archiving, as their reviewers have long since moved past Adobe versions that can only handle version 1.4.

If you are submitting to regional authorities in Europe, you may wish to check with those authorities and also to run your submission through the Belgian Registration file validation.    Also keep in mind that one of your biggest issues could be literature references, which may be supplied to you in PDF format.  If it’s not possible to “save down” to V1.4, worst case you might have to scan to V1.4.

New Draft eCTD Guidance for EU: Analysis

posted by mr.erhabi511 @ 5:32 PM
Tuesday, May 26, 2009

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 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.

*** Update: the links below, which had been working fine between when this was posted and today (May 18), appear to be no longer functional.  Possibly the AAPS had not meant them for public consumption; however, I have not been contacted by them so I don’t know this for sure.  Apologies that the links no longer work but they are out of my control.  – K.C. ***

You could contact the AAPS, or see if you can track down the speakers and ask them for the presentations. The following email addresses were included:

Health Canada:  

The AAPS Workshop on Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!  was held March 9-11, 2009.  There were some great presentations, and best of all they are publically available. The agenda contains links to the presentations.

All the presentations were good but some of the highlights for me appear below.  There’s great information on Japan and Health Canada that has been rather hard to locate recently, and lots of discussion about some of the more puzzling and problematic aspects of eCTD as they relate to CMC in particular – so you know there will be discussions about metadata, granularity, and the tradeoffs in structuring M2 and M3.

Updates from the Regulators

Evdokia Korakianiti  of EMEA presented eCTD: EMEA Experiences  containing FAQs received by the EMEA, concerning CMC metadata, CEPs, ASMF – plus some great key messages for industry. 

The presentation eCTD in Japan by Harve Martins has lots of good info on eCTD in Japan that has not been readily available – such as details and examples on lifecycle (handled in an accumulative approach in Japan), Module 1 TOC, cover letter and form information, module 5 unique requirements, validation details, submission instructions, etc.   I’ve reproduced the update on the number of sequences received in Japan (keep in mind that a reference application is something like Health Canada’s co-submission – in effect a review aid for a paper submission.) MLHW eCTD Submissions

 Health Canada’s Vianney Caron presented e-Submissions at Health Canada which reviewed HC’s history and future direction with eCTD, challenges and issues with CMC documents, especially the QOS.  Health Canada also presented statistics on the number of eCTDs they have been receiving (they now get about 7% of their regulatory activities in eCTD format).    health-canada4 

Regulatory Activities in eCTD format (NDS, SNDS, ANDS, SANDS, NC) 

About 8.2% of submissions are currently failing validation, well down from the 31% experienced in early days.  Following the lead of FDA and EMEA, they have provided their top 10 list of validation errors:

1. Inactive bookmarks -no link destination
2. Inactive hyperlinks -no link destination 
3. External links -pointing to the folder or destination that does not exist in the folder structure on the CD/DVD. The folder or destination would only exist in the sponsor's repository.
4. Incorrect naming of the 3011 form (correct name is hc-sc-3011-en.pdf)
5. Unreferenced files in the index.xml or ca.regional.xml
6. Life cycle management of the document: invalid file reference or no previous ID found
7. Subfolders created in ca regional folder
8. Missing top level folder
9. Missing attestation letter; content as per eCTD Guidance, letter needs to be dated and signed
10.Printed content of MD-5 Checksum does not match the one in the index-md5.txt file 

Health Canada strongly recommends electronic submissions in eCTD format, and they plan to expand the existing architecture to support as many application types across product line as possible.  Some of their next steps in support of eCTD include:

  • Perform assessment of the hybrid pilot
  • Widen the scope to more electronic data in eCTD format
  • Implement two-way secure electronic communication (secure channel, secure email and gateway)
  • Improve tracking system and integrate it with a workflow system
  • Strengthen international collaborations
  • Announce a date (TBD) for accepting electronic-only submissions

The eCTD Industry Forums –Europe presentation by Phyllis Thomas of AstraZeneca UK summarizes discussions by the CMC eCTD informal industry group and EFPIA eCTD-Q topic team.  It has lots of discussion about metadata and repeating section issues, including illustrative examples.  It also discusses issues and areas that lack clarity that have been passed on as Q&A and in turn referred to the harmonization taskforce (some of them not yet resolved). 

ICH & Regional Guidance and Terminology by Hans van Bruggen provides a comprehensive summary of eCTD status in many regions (including individual EU countries).  Again, this is information that is hard to find and nearly impossible to find in one place. 

Industry Best Practices

In Points to Consider for Case Studies in Lifecycle-Biologics, Colleen Godshall of Merck addresses some of the issues that have always caused me to hold CMC people in awe: however do they perform impact analysis of change and manage the approvals and notifications requirements that are so different in every region?   Concrete examples are provided, such as “Adding a New Air Handler to a Class 100 Area used to manufacture multiple vaccines”.  Ms. Godshall also talks about managing 3.2.A.1 for both US applications, which allow cross-applikcation linking, and International Marketing Authorizations, which do not.

A presentation by Pamela Cafiero  of  Boehringer Ingelheim, Simultaneous eCTD Applications in US and EU: Similarities/Differences and the Reasons Behind them, gives detail on a subject I’ve been asked about many times – what are the real differences in content between US and EU Module 3?  She also gives recommendations about document identification (header/footer), Referencing between CMC documents, referencing and linking within Module 3 (her minimalist approach resulted in about two dozen links between Module 3 documents and was the same in US and EU), and recommendations and examples of CMC metadata, leaf titles and the relationships between them.

Phyllis Thomas of AstraZeneca UK also spoke about USING MODULE 3 (FOR INDs).  She focused on encouraging the use of granularity in IND M3 (even though it is not required) and some special considerations for INDs such as Placebos, Comparators, and Introductory CMC text.  

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