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									EU Region Question and Answer and Specification Change Request Document

                                          Version 1.17

                                             March 2009

                                    Document Change History
          Version Number    Date                                           Description
       Version 1.0         Jul-04    Initial baseline after reviewing existing questions
       Version 1.1         Sep-04    Change Request added (EFPIA)
       Version 1.2         Jun-05    New Change Requests and Q&A added, plus ICH Q&A referred for regional advice

       Version 1.3         Sep-05    New Change Requests 09, 10, 11, 12, 13 added
       Version 1.4         Nov-05    New Change Request 14 added
       Version 1.5         Dec-05    Q&A 14 added
       Version 1.6         Dec-05    Updated after release of eCTD v1.1
       Version 1.7         Mar-06    CRs 15-16-17-18 Added for TIGes-J-24
       Version 1.8         Jun-06    Review of document carried out for TIGes
       Version 1.9         Nov-07    Comprehensive addition of accrued change requests and review of summaries

       Version 1.10        Jan-08    Further updates for publishing on EMEA e-subs website
       Version 1.11        Jan-08    More updates for publishing on EMEA e-subs website (whilst review of CRs/Q&A
                                     is ongoing)
       Version 1.12        Mar-08    Q&As 9, 12, 15-21 added confirmed after TIGes-J-32
       Version 1.13        Jun-08    CRs and QA 22 added for TIGes 33, general update after publication of EU M1
                                     specification v1.3
       Version 1.14        Dec-08    Comments from Interlinking Group on all CRs assigned to this group, and comments
                                     from Dec. TIGes. Addition of CR-2008-12-10
       Version 1.15        Mar-09    CRs added for TIGes 35. Full review of outstanding change requests and
                                     assignments. Introduction of colour coding for open/closed CRs
       Version 1.16        Mar-09    Updated after Interlinking meeting review of all assigned CRs
       Version 1.17        May-09    Updated after Interlinking meeting of April 2009 and publication of updated
                                     validation criteria May 2009, update of CP dossier requirements April 2009,
                                     publication of Harmonisaed Guidance May 2009
Introduction
This document is a summary of questions and change control requests reviewed by the Telematics Implementation Group electronic submissions
(TIGes) on the eCTD Specification, PIM and electronic Application Forms (eAF). Questions are listed with with an approved answer. Change
control requests are listed with details of the person, company or organisation who submitted the request, along with details of the actions taken
and status of the request.

The change control requests and Q&As here relate to EU specific aspects of the eCTD and EU regional electronic submission formats. Reference
should be made to the ICH Q&A and Change Requests tracking document for matters that affect all regions (http://estri.ich.org/ectd/).


This document will be updated as the specification undergoes change control or as new questions are submitted to the TIGes.

Key to Q&A Worksheet
Each question is numbered. The question is written out in full and a reference to the change control procedure item that caused the question to be
asked is listed. An official answer is given. The approval date for the answer is listed.


Key to Change Requests Worksheet
Each change request or question received is numbered. A subset of the change request or question information is copied from the "European
eCTD Standards Q&A and Change Request Form", including the name and organisation of the person raising the request and the description of
the change or the question in full. Any comments arising during the analysis of the issue by TIGes are recorded as well as the Status and
Action(s) resulting.

CR closed : Either action progressed to completion in EU, Referred to ICH M2 and completed, Rejected and not progressed
CR open : On-going within EU or Referred to ICH M2 still on-going
#                              Question                                                                    Answer                                          Approval
                                                                                                                                                             Date
1 What is the EU's position on the use of XML for the content of the   In line with the general principles of the ICH eCTD Specification Document, it is   Mar-2007
    submission instead of PDF and/or RTF?                              intended that XML will become the submission format for administrative forms
                                                                       and product information documents as they contain structured data. The long
    This question was generated by EU Change Request A001              term goal of this development is the normalisation of data in Module 1. As the
                                                                       XML documents become available for practical implementation, they will be
                                                                       introduced into Module 1 and the current file formats may be replaced after a
                                                                       transition period.

2 Can further guidance be given on the acceptable formats for          With respect to product information (PI) documents, the currently acceptable file   Mar-2007
  product information in the eCTD?                                     formats are indicated in the EU Module 1 specification. When generating
                                                                       product information files for the Centralised, Mutual recognition and
    This question was generated by EU Change Request A002              Decentralised Procedures, QRD templates as issued by the EMEA should be
                                                                       used. For National Procedures, refer to national guidance. The EU will be
                                                                       moving into the direction of an XML approach for the exchange of product
                                                                       information as part of the Product Information Management (PIM) project which
                                                                       is currently being implemntated in the Centralised Procedure. For additional
                                                                       details on the PIM project, see: http://pim.emea.europa.eu


3 Is the submission of application forms as XML documents              It is the intention of the EU to provide XML standards for application forms. The   Mar-2007
  acceptable?                                                          specifications for new and variations forms have been issued and can be
                                                                       accessed at
    This question was generated by EU Change Request A003              http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm. An
                                                                       electronic version of the renewals form is currently under development. Refer to
                                                                       national guidance regarding the applicability of the XML Application Forms.


4 What is EU's position on the use of e-signatures in the eCTD?        A crucial part of pure electronic communications between the pharmaceutical         Mar-2007
                                                                       industry and regulatory agencies and authentication of electronic submissions
    This question was generated by EU Change Request A004              or documents contained in electronic submissions will be the use of digital
                                                                       signatures. Currently the EU is developing a (long-term) strategy to implement
                                                                       digital signatures. As yet, digital signatures cannot be used or supported in
                                                                       electronic submissions in the EU.
#                              Question                                                                    Answer                                         Approval
                                                                                                                                                            Date
5 How should an applicant handle a Type I variation within an eCTD? The Notice to Applicants group has issued a CTD Q&A regarding the placement           Mar-2007
                                                                    of documents within the CTD structure for Type I variations. The eCTD should
  This question was generated by EU Change Request 0003             also be constructed using these principles. The Q&A (4c) can be accessed at
                                                                    http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-
                                                                    2/b/ctd_qa_05_2006.pdf


6 The EU Module 1 Specification allows 3 procedures (National,          The EU Module 1 specification defines the submission types that are part of the   Mar-2007
  Centralised and Mutual recognition procedure). How should             eCTD (V1.2.1, p10). The submission type to be used in this instance is
  “Community referrals” be handled, which type of procedure should      'arbitration'. [Note, since this question was originally received, the EU has
  be used respectively?                                                 added the Decentralised Procedure as an acceptable submission procedure
                                                                        type.]
    This question was generated by EU Change Request 0004
7 I am trying to understand the complete scope of what submissions      The EU Module 1 specification defines the submission types that are part of the   Mar-2007
  are to be                                                             eCTD (V1.2.1, p10). All of these submission types are covered, including
  required as CTD/e-CTD submissions in the EU.                          Follow-up Measures and PSUR submissions.
  From reading some background on the topic, I think the scope may
  include:
  - all new applications
  - all variations
  - all response documents (MRP and CP response documents)
  - all renewals
  but does not include
  - submissions of data as part of a FUM but which is not a variation
  - PSUR submissions
  Can you please confirm/correct this understanding.

    This question was generated by EU Change Request A007
#                               Question                                                                       Answer                                           Approval
                                                                                                                                                                  Date
8 I am seeking information on the structure of the eCTD response to        The May 2006 version of the Notice to Applicants                                     Mar-2007
  list of questions dossier. In the eCTD EU module 1 specifications        (http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/ctd_05-
  v1.0, it is stated that responses to questions can be included in        2006.pdf) now defines a specific section in Module 1 for Responses to
  Module 1. At the Annex 2 level, it is stated that response               Questions, what to include in Module 1 and what to include in Modules 2-5. The
  documents should be attached to the Cover Letter (1.0). However,         EU Module 1 specification Version 1.2.1 now includes the section for
  no recommendation is given with regard to the organisation of the        Responses to Questions. The CTD guidance and eCTD specification together
  table of contents, nor to the names and organisation of the files etc.   should give adequate direction for applicants to construct a Responses to
  Do these recommendations exist?                                          Questions dossier in eCTD format. The filenaming recommendation is also
                                                                           included in the EU specification v1.2.1.
    This question was generated by EU Change Request A008

9 M3 requires each substance-manufacturer and drug product to be           The ICH CTD guidance recommends that the applicant repeat the complete               Feb-2008
  added in a separate subfolder. How should a product be added to          Module 3.2.S for each drug substance that makes up the drug product. The
  the structure if it has multiple substances?                             ICH eCTD specification allows the repeat of the Module 3.2.S within the XML
                                                                           backbone. Therefore, the applicant should create the eCTD in this way.
    This question was generated by EU Change Request A009
10 Where can node extensions be used in a EU eCTD submission?      Node extensions may be used where additional navigation in the XML backbone                  Mar-2007
                                                                   is required. The primary place where they may be used is in Module 5 where a
    The question was generated by ICH change request 00560 and the node extension for each study may be useful so as to allow multiple files for a
    response to ICH eCTD Question 28. This is recorded as EU       single study to be grouped together and separated distinctly from other studies.
    Change Request A010.                                           For Module 4 where there are multi-file reports this can also be useful. Other
                                                                   places where they can be useful is in Module 1 to differentiate between PI
                                                                   documents provided in PDF and those provided in RTF/Word and in Module 5
                                                                   to differentiate reports associated with a different dosing regimen for the same
                                                                   indication.

                                                                           However, the use of node extensions should be limited to those areas where it
                                                                           is critical and consideration should be given regarding the impact of the view for
                                                                           the reviewer since the inconsistent use of node extensions can lead to
                                                                           unanticipated effects in the cumulative view of a submission.

                                                                           See separate Q&A #10 worksheet for more details
#                                Question                                                                   Answer                                         Approval
                                                                                                                                                             Date
11 In the eCTD for the EU, are applicant provided style sheets    Little advantage is to be gained by the use of custom stylesheets. The XML               Mar-2007
   allowed?                                                       instance can only point to one stylesheet and the inclusion of a reference to a
                                                                  stylesheet that is not the regional one would prevent the agency using the
   The question was generated by ICH change request 00710 and the official EU stylesheet. It is therefore recommended not to submit customised
   response to ICH eCTD Question 30. This is recorded as EU       stylesheets.
   Change Request A011.
12 Can clearer guidance be provided regarding how to use the      A 'regulatory activity' is a logical unit of submission activity (eg, a Type II          Feb-2008
   Related Sequence attribute during the lifecycle of the eCTD?   Variation) with a defined start and end point (eg initial submission to final
                                                                  approval). In the eCTD world, this will consist of all the sequences that together
   This question was generated by EU Change Requests A012 and     make up the lifecycle of that particular 'regulatory activity‟.
   QA-20070628-01
                                                                  The related sequence attribute should always be left blank for new applications
                                                                  or new regulatory activities (eg variations, PSURs). When submitting lifecycle
                                                                  sequences within an existing activity, the related sequence attribute should be
                                                                  populated with the sequence number of the first sequence in the activity,
                                                                  regardless of how many sequences make up the activity. The related sequence
                                                                  attribute should be considered independent of any modified file attributes in a
                                                                  submission. For example, if a sequence 0010 modifies files (leaves) in
                                                                  sequence 0008 and 0009, the entry for related sequence in sequence 0010
                                                                  should be the sequence number that started the regulatory activity that 0010
                                                                  falls within, which will not necessarily be sequence 0008 or 0009.

                                                                        For examples, see the table in Worksheet QA 19.
13 ICH has issued a list of items to be checked by the applicant before A list of validation criteria specific to the EU has been prepared by the EURS     Jan-2008
   a submission is sent to the agency (Q&A 36). Could a list also be    Implementation Group and is to be published separately on the esubmission
   produced for EU regionally specific items that should also be        website http://www.esubmission.europa.eu
   checked?

    This question was generated by EU Change Request A013
14 What is the EU regional guidance relating to the ability to cross-    In the EU it is possible to refer to a file located in the same sequence or any   Mar-2007
   reference from one sequence to files in another sequence?             previous sequence of the same eCTD. It is not possible to refer to other eCTDs.

    The question was generated by ICH change request 01080 and the
    response to ICH eCTD Question 37. This is recorded as EU
    Change Request A014.
#                               Question                                                                       Answer                                     Approval
                                                                                                                                                            Date
15 How is the applicant advised to handle technical (eCTD                  If an eCTD fails technical validation, then a replacement sequence must be     Feb-2008
   specification) and business (content) validation changes in the         provided, since an invalid sequence cannot be loaded into an agency‟s review
   eCTD                                                                    tool. If, once technical validation has been completed, content validation
                                                                           identifies missing sections or administrative errors, then an additional new
    This question was generated from EU Change Request QA-                 eCTD sequence should be provided (a lifecycle sequence) correcting these
    20061120-01                                                            errors, with replacement or additional new documents as required. The
                                                                           applicant should not send a replacement of the original sequence.


16 The EU eCTD Specification v1.2.1 states that the variable               No it is not acceptable to use a hyphen. In cases where differentiation is     Mar-2008
   component of filenames should be a “meaningful concatenation of         needed it is suggested that the word 'point' is used in the filename eg.
   words without separation and should be kept as brief and                1point5mg
   descriptive as possible” but also specifies that hyphens (“-“) should
   not be used within these variable components. There are
   occassions where there needs to be differentiation between
   documents, for example, strength (1.5mg or 15mg). Is it
   acceptable that under such circumstances to use a hyphen to
   differentiate between documents.

    This question was generated by EU Change Request CR-
    20061221-01

17 The EU eCTD Specification v1.2.1 states that the envelope element The envelope should be repeated for each member state and 'common' should            Feb-2008
   of MRP or DCP submissions could be assigned a country attribute not be used. The specification will be updated at the next version to correct this.
   value "common" when the same sequence is being submitted to
   multiple countries. Isn't it more appropriate to utilise a separate
   envelope for each Member State?

    This question was generated by EU Change Request CR-
    20070309-01
#                               Question                                                                    Answer                                           Approval
                                                                                                                                                               Date
18 Is it necessary to include statements in the CTD/eCTD justifying the For new applications, detailed statements justifying absence of data or specific     Mar-2008
   absence of data? If so, where should these statements be placed in CTD sections should be provided in the relevant Quality overall summary and/or
   the CTD structure?                                                   non-clinical/clinical overviews (Module 2.3, 2.4, 2.5). Note that placeholder
                                                                        documents highlighting 'no relevant content' should not be placed in the eCTD
   This question was generated by EU Change Request QA-                 structure, as these would create a document lifecycle for non-existent
   20070627-01                                                          documents and unnecessary complication and maintenance of the eCTD.




19 In Europe does the applicant need to update attributes in the eCTD   Reference is made to ICH Q&A #3. It is not possible to update the attributes         Mar-2008
   backbone during the life an application, for example, if the         nor is it necessary to attempt workarounds such as deleting existing documents
   manufacturers name changes, the proposed name of the dosage          and resubmitting with new attributes. The recommendation is to retain the
   form is not accepted or an excipient is granted a pharmacoepial      obsolete entry and to rely on the document content to explain the current details.
   name.
   This question was generated by EU Change Request QA-
   20070816-01
20 Should eCTD Module 1 section "additional data" be empty for          Yes. The Notice to Applicants CTD Q&A #4C states that the 'Additional Data"          Mar-2008
   EMEA centralised procedures?                                         should only be used for information required for National, MRP and
   This question was generated by EU Change Request CR-                 Decentralised Procedures and is therefore not applicable for the Centralised
   20071002-01                                                          Procedure except during a transition period when an old version of a DTD is
                                                                        being used to support inclusion of a newly defined section of Notice to
                                                                        Applicants ie. paediatric data which will be included in EU specification Module
                                                                        1 v1.3 as a new section 1.10 Information relating to Paediatrics.
#                               Question                                                                      Answer                                        Approval
                                                                                                                                                              Date
21 Can content files that are included in the index.xml (ICH Modules 2-   Yes. For appendices to the application form which may also be located in          Mar-2008
   5) also be referred to in the eu-regional.xml?                         module 3, it is recommended to create a leaf in the eu-regional.xml that points
   This question was generated by EU Change Requests CR-                  to the content located in module 3 e.g. Flow Chart of the Manufacturing Sites,
   20070906-01 & CR-20070927-01                                           and Ph.Eur Certificate. Other scenarios where this approach should be used
                                                                          include type Ia and Ib variations, where content is requested in module 1 which
                                                                          is available in pre-existing locations in module 3, e.g. copy of the approved
                                                                          specification.
22 In the NtA Section 2.7.6 Synopses of Individual Studies requires       It is acceptable either to include copies of the synopses for each study in       Apr-2009
   that the synopses are included in this section but the ICH eCTD        Section 2.7.6 or to provide hyperlinks to synopses located in Module 5 without
   Specification suggests that it would be satisfactory to provide        providing copies in section 2.7.6. In either case a Listing of Clinical Studies
   hyperlinks to the synopses located in Module 5. Could clarification    should be provided and this should include hyperlinks to the first page of each
   be provided regarding what is acceptable for the eCTD in the EU?       synopsis.
   This question was generated by EU Change Request CR-20090126
Node Extensions
As noted in the ICH Q&A 28, the use of node extensions is to be clarified in regional guidance. This short document
proposes how node extensions may be used in EU eCTDs.

Assumption: The applicant is not planning to create a single eCTD for Modules 2-5 that can be used in all regions. As
noted, the FDA expressly forbids the use of node extensions, therefore, if the these are inserted anywhere in Modules 2-5
the eCTD will be invalid in the US.

Node extensions are a way of providing extra organisational information to the eCTD. The node extension should be
visualised as an extra heading in the CTD structure and should be displayed as such when the XML backbone is viewed.
The following are the proposed rule for the use of node extension in the EU:

1. Node extensions must not be used where there is an ICH specified node extension
e.g. indication, manufacturer, drug substance, drug product are all ICH specified node extensions

2. Node extensions must only be used at the lowest level of the eCTD structure e.g. a node extension can be used at the
level 5.3.5.1 but must not be used at the level 5.3
It was noted that the eCTD DTD currently allows node extensions to be placed at any level, eventually, this may need to be
amended in the ICH specification.

3. Node extensions are mainly to be used to group together documents made up of multiple leaf elements
e.g. a clinical study made up of separate files for the synopsis, main body and individual appendices could be grouped
together under a node extension with the Study Identifier as its Title attribute

4. Once added, node extensions must be maintained over the entire life of the eCTD lifecycle
e.g. if a node extension is used in sequence 0000 to group files for a study report in Module 5.3.5.1, then any files
submitted in a later sequence must also be placed under a node extension, even if only one file is submitted

5. Node extensions may be nested as this is allowed by the eCTD DTD. However, as noted in point 2, the first node
extension must be at the lowest level in the eCTD structure.
e.g. in Module 5.3.7 a node extension may be added to group together files with the Study Identifier as Title attribute.
Further node extensions may be added as children of the Study Identifier node, separating CRFs from individual patient
listings.

Note : This description has been included in EU Specification v1.3
                          Example of how the Related Sequence should be used
   Sequence                         Submission Description                         Related                             Comment
                                                                                   Sequence
0000             Original MAA application                                       <none>
0001             Day 121 Responses to questions on the original application     0000          This is a continuation of the regulatory activity initiated in
                                                                                              0000 and so the related sequence points to the beginning of
                                                                                              that activity
0002             Day 181 Responses to further questions on the original         0000          This is a continuation of the regulatory activity initiated in
                 application                                                                  0000 and so the related sequence points to the beginning of
                                                                                              that activity
0003             Type II variation for treatment of pain indication             <none>        This is the beginning of a new regulatory activity and so no
                                                                                              related sequence is included
0004             Type II variation for a change in manufacturing site (Westferry) <none>      This is the beginning of a new regulatory activity and so no
                                                                                              related sequence is included
0005             Responses to questions on Type II variation for the pain       0003          This is a continuation of the regulatory activity initiated in
                 indication                                                                   0003 and so the related sequence points to the beginning of
                                                                                              that activity
0006             Responses to questions on Type II variation for change in      0004          This is a continuation of the regulatory activity initiated in
                 manufacturing site (Westferry)                                               0004 and so the related sequence points to the beginning of
                                                                                              that activity
0007             Line extension to introduce a new dosage form (iv solution)    <none>        This is the beginning of a new regulatory activity and so no
                 that amends information provided in the original application                 related sequence is included
                 and the manufacturing change variation
0008             Updated, agreed, product information taking into account new   0003          This is the completion of the new indication (pain) activity
                 indication (pain)
0009             Updated, agreed product information for the iv formulation     0007          This is the completion of the new dosage form (iv
                                                                                              solution) activity

Note : This description has been included in EU Specification v1.3
                                                            EU eCTD Specification Change Requests
 #     Requestor      Specification                                  Description                                                     Comments                        Status              Action                        Group Where Action
                       Component                                                                                                                                                                                       is Sitting
A001               eCTD EU Module 1   What is the EU's position on the use of XML for the content of the             Change request added retrospectively to allow Implemented in EU     Implement in v1.3:
                   Specification      submission instead of PDF and/or RTF?                                          tracking of the Q&A process                   M1 v1.3               Answered as Question #1.
                                                                                                                                                                                         Clarify in Appendix 2 row 6
                                                                                                                                                                                         (comments section)


A002               eCTD EU Module 1   Can further guidance be given on the acceptable formats for product            Change request added retrospectively to allow   Answered in Q&A     Answered as Question #2
                   Specification      information in the eCTD?                                                       tracking of the Q&A process
A003               eCTD EU Module 1   Is the submission of application forms as XML documents acceptable?            Change request added retrospectively to allow   Answered in Q&A     Answered as Question #3
                   Specification                                                                                     tracking of the Q&A process
A004               eCTD EU Module 1   What is EU's position on the use of e-signatures in the eCTD?                  Change request added retrospectively to allow   Implemented in EU   Implement in v1.3:
                   Specification                                                                                     tracking of the Q&A process                     M1 v1.3             Answered as QAA #4.
                                                                                                                                                                                         Include a new section
                                                                                                                                                                                         alongside 'acceptable
                                                                                                                                                                                         formats' p.6 stating that
                                                                                                                                                                                         reference should be made
                                                                                                                                                                                         to national guidance on the
                                                                                                                                                                                         use of e-signatures.


A007               eCTD EU Module 1   I am trying to understand the complete scope of what submissions are to be     Change request added retrospectively to allow Answered in Q&A       Answered as Question #7
                   Specification      required as CTD/e-CTD submissions in the EU.                                   tracking of the Q&A process
                                      From reading some background on the topic, I think the scope may include:
                                      - all new applications
                                      - all variations
                                      - all response documents (MRP and CP response documents)
                                      - all renewals
                                      but does not include
                                      - submissions of data as part of a FUM but which is not a variation
                                      - PSUR submissions
                                      Can you please confirm/correct this understanding.



A008               eCTD EU Module 1   I am seeking information on the structure of the eCTD response to list of      Change request added retrospectively to allow Answered in Q&A       Answered as Question #8
                   Specification      questions dossier. In the eCTD EU module 1 specifications v1.0, it is stated   tracking of the Q&A process
                                      that responses to questions can be included in Module 1. At the Annex 2
                                      level, it is stated that response documents should be attached to the Cover
                                      Letter (1.0). However, no recommendation is given with regard to the
                                      organisation of the table of contents, nor to the names and organisation of
                                      the files etc. Do these recommendations exist?


A009                                  M3 requires each substance-manufacturer and drug product to be added in        Change request added retrospectively to allow Answered in Q&A       Answered as Question #9
                                      a separate subfolder. How should a product be added to the structure if it     tracking of the Q&A process
                                      has multiple substances?
                                                                   EU eCTD Specification Change Requests
 #       Requestor           Specification                                  Description                                                       Comments                          Status              Action                         Group Where Action
                              Component                                                                                                                                                                                            is Sitting
A010   The question was   eCTD EU Module 1   Clarification should be provided by all ICH regions as to whether node         November 2004: The use of node extensions           Implemented in EU   Implement in v1.3:
       generated by ICH   Specification      extensions can be used in Modules 2-5                                          should be discussed with FDA on a case by           M1 v1.3             Answered as Q&A #10.
       change request                        The ICH spec allows node extensions to be used in Modules 2-5 and their        case basis. Other regions are able to accept                            Include on p.7 an additional
       00560                                 use in Module 1 is a regional matter. FDA states that node extensions are      appropriate use of node extensions in                                   section with agreed text
                                             not supported in any part of the submission and this therefore invalidates     compliance with the eCTD specification (i.e.
                                             the ICH spec. Experience on production of submissions for Europe               their use is discouraged unless there is no
                                             demonstrates that node extensions are required to deliver a navigable          other feasible means to submit the
                                             structure for Modules 4 and 5. At present this means that eCTDs are not re-    information).
                                             usable across regions and thus will create significant amounts of rework for
                                             industry. FDA should accept node extensions in Modules 2-5.                    May 2005: Referred to EU and MHLW
                                                                                                                            regional guidance for specific instances where
                                                                                                                            it can be used.

                                                                                                                            June 2005: Proposal to come from EFPIA as
                                                                                                                            to how node extensions may be accepted in
                                                                                                                            the EU. Clarification: FDA strongly
                                                                                                                            discourages node extensions. ACTION: EFPIA
                                                                                                                            to circulate the proposal to TIGes-J.

A011   The question was   eCTD EU Module 1   Are applicant provided style sheets allowed?                                   May 2005 - referred to EU and MHLW for              Implemented in EU   Implement in v1.3:
       generated by ICH   Specification                                                                                     regional guidance                                   M1 v1.3             Answered as Question 11.
       change request                                                                                                                                                                               Put a comment in appendix
       00710                                                                                                                June 2005: Applicant stylesheets are                                    2,row 72.
                                                                                                                            accepted in the EU. However, there are
                                                                                                                            improvements to be documented and made to
                                                                                                                            the EU stylesheet to ensure that its features
                                                                                                                            meet requirements. If necessary changes are
                                                                                                                            made, the use of company stylesheets should
                                                                                                                            be strongly discouraged.

A012   The question was   eCTD EU Module 1   Can further clarification be provided on the related sequence element?         May 2005 - referred to EU and MHLW for              Answered in Q&A     Answered as Question #12
       generated by       Specification                                                                                     regional guidance
       change request
       00890                                                                                                                June 2005: To be covered by the EFPIA White
                                                                                                                            Paper on eCTD LCM.

                                                                                                                            Feb 2008 : Answered as Question #12
A013                      eCTD EU Module 1   From the eCTD experience of the IWG, what parts of the Specification are       Based on experience, there have been                Answered in Q&A     Answered as Question #13
                          Specification      commonly misinterpreted that would prevent my eCTD message from being          different interpretations of the eCTD                                   and covered by EU
                                             viewed by another applicant/regulator?                                         Specification that have prevented timely                                Validation criteria.
                                                                                                                            exchange of eCTD submissions. Those
                                                                                                                            creating and viewing eCTD messages should
                                                                                                                            adhere to the eCTD Specifications (ICH and
                                                                                                                            regional) and consult with regional authorities
                                                                                                                            to avoid these problems. The items in the
                                                                                                                            following list already exist in the Specification
                                                                                                                            3.2, but have been summarized here to
                                                                                                                            alleviate these problems. Adherence to these
                                                                                                                            items is technically necessary to exchange
                                                                                                                            eCTD messages. Extra controls might hinder
                                                                                                                            the exchange of eCTD messages. The IWG
                                                                                                                            will continue to monitor eCTD implementation
                                                                                                                            to provide additional clarity.
                                                                                                                            May 2005 - referred to EU and MHLW for
                                                                                                                            regional guidance

                                                                                                                            June 2005: Need EU validation criteria.
                                                                        EU eCTD Specification Change Requests
 #        Requestor            Specification                                     Description                                                        Comments                        Status              Action                      Group Where Action
                                Component                                                                                                                                                                                           is Sitting
A014   Generated by ICH                          What is the EU regional guidance relating to the ability to cross-reference                                                        Answered in Q&A     Answered as Question #14.
       Q&A # 37.                                 from one sequence to files in another sequence?



0001   Andrew Marr          EU DTD v1.0,         Experience is showing that when a number of lifecycle documents have              It may be possible to have an additional         Implemented in EU   Opened 19-09-2004
       (EFPIA)              Specification v1.0   been created it is not possible to know what each sequence is about with          attribute assigned to the submission type        M1 v1.1             Agreed 24-09-04
                                                 physically opening the sequence documents and reading the Cover Letter.           „submission description‟. This could be either
                                                 Industry is already considering requesting the vendors to provide some            optional or mandatory dependent upon                                 Dec 05: Implemented in
                                                 additional description to assist in creation of the applications and we           submission type.                                                     eCTD Spec v1.1 - new
                                                 understand that at least the EMEA is adding a description to this Docubridge                                                                           element 'submission-
                                                 records. It would be logical to standardise on an additional attribute that the                                                                        description' added to
                                                 applicant can complete for there own records and that the agencies can                                                                                 envelope.
                                                 make use of in their reviews.For example an applicant could use a simple
                                                 description of „Excipient change‟ – against a Type II variation submission
                                                 type. It this way a set of simple descriptions will be built up over time that
                                                 will assist differentiation between sequence content without the necessity of
                                                 opening a cover letter.


0002   Sandoz (Ron de       Application Form     The EAF does not allow for the form to be combined for all member states                                                           Deferred            Referred to NtA with MRFG eAF
       Boer)                                     during MRP subm. For a paper based subm this combined AF has been                                                                                      representatives.
                                                 requested by some and has been accepted by all EU member state                                                                                         R. de Boer to split the CR
                                                 agencies. This change request is made to enable the AF to be used during                                                                               into those points that are
                                                 MRP submissions. Some of the requests made below are suitable for none                                                                                 nice to have and those
                                                 MRP subm as well.                                                                                                                                      which are essential
                                                 Generic apps - It should be possible to include reference medicinal                                                                                    requirements
                                                 products for multiple MSs. In case of an MRP this needs to be filled in for
                                                 each MS, because the reference product marketed in each MS is different.
                                                 This change is relevant for MRP only.
                                                 It should be possible to include multiple medicinal products used in the BE
                                                 study.
                                                 All submission types. Proposed dispensing/classification - It should be
                                                 possible to select both “subject to medical prescription” and “not subject to
                                                 medical prescription”.
                                                 It should be possible to include multiple marketing authorisation holders.
                                                 CP&MRP It should be possible to include multiple persons authorised for
                                                 communication after authorisation.
                                                 It should be possible to include multiple qualified persons for
                                                 pharmacovigilance .
                                                 It should be possible to include multiple persons responsible for
                                                 scientific services.


0003   EFPIA (A. P. Marr)                        How should an applicant handle a Type I variation within and eCTD?           Referred as Q&A to Notice to Applicants Group Answered in Q&A             Answered as Question #5
                                                 Guidance provided in the Notice to Applicants for Type II variations states                                                                            and in CTD Q&A.
                                                 that they should be organised according to CTD but for Type IA/IB variations
                                                 it simply states that they should be organised according to CTD, where
                                                 applicable. This suggests that there will be occasions when it is not
                                                 applicable to utilise a CTD structure and under those circumstances it will
                                                 not be possible to use the eCTD. Clarification should be provided on how to
                                                 minimise incompatibilities with the eCTD since it is impossible to construct
                                                 an eCTD that is not CTD compliant
                                                                      EU eCTD Specification Change Requests
 #        Requestor        Specification                                       Description                                                      Comments                      Status                Action                         Group Where Action
                            Component                                                                                                                                                                                              is Sitting
0004   Fujisawa GmbH    EU Module 1 envelope Notice to applicants “Volume 2A/ Procedures for marketing                      More understanding of eCTD LCM required for Answered in Q&A             Answered as Question #6.
       (M. Hamzakadi)                        authorisationChapter 1/ Marketing Authorisation/February 2004” describes 4 resolution                                                                  Refers to list of submission
                                             types of Marketing authorisation procedures (p.3-6) as follows: - Centralised                                                                          types (already responded
                                             procedure - Mutual recognition procedure- Independent National procedures- Referred to Notice to Applicants Group                                      to in CR-20070926-01).
                                              Community referrals. In comparison with this, the appendix 1: Envelope
                                             Element Description” of the EU Module 1 Specification v1.0 document do
                                             not include the “Community referrals” for the element “procedure” as valid
                                             value. The list of valid values for the “type” of procedure for the submission
                                             should be adapted i.e. a new value “community referrals” should be added if
                                             possible?


0005   EMEA (T. Buxton) eCTD EU Module 1       In the same way as the electronic application form permits information to be     In fact, the acceptance of 'Other file formats  Implemented in EU   Dec 05: Implemented in
                        Specification          submitted using XML, so the PIM DES does the same for product                    in accordance with the PIM DES' should be       M1 v1.2.1           eCTD Spec v1.1 - accepted
                                               information. The current EU Module 1 specification permits PDF and RTF as        detailed, as this standard includes more than                       file formats amended.
                                               formats for product information, but not XML. For administrative information,    XML (additional documents that can be                               Oct 06: Updated in eCTD
                                               however, XML is permitted. Suggestion : Include XML as an accepted format        attached with the XML)                                              Spec v1.2.1 - accepted file
                                               for the “labelling text” item                                                    Furthermore the specification has been                              formats amended
                                                                                                                                updated to recognise that PIM files are
                                                                                                                                submitted in archive format as ZIP or TGZ files
                                                                                                                                that contain XML and other file formats.



0006   Datafarm (S.     eCTD EU Module 1       The specifications do not provide folder structure requirements for UTIL         Retain separate util folder for components that Implemented in EU   Oct 06:
       Kumar)           Specification          folder that includes STYLE and DTD folders. The screen shots are good            can be submitted outside eCTD e.g. e-AF and M1 v1.2.1               Implemented in eCTD Spec
                                               and include a STYLE folder under UTIL folder under m1/eu. See page 25 to         PIM. For those regional components that are                         v1.2.1, cell 72, p.28
                                               29.Please note that the STYLE folder is already present under submission         always submitted as part of eCTD, use global
                                               folder under UTIL folder e.g. eu12345/0000/util/style. In the same location      util folder to obviate need for regional util
                                               we have a DTD folder.This structure is clear and consistent across all           folder. More testing required of PIM container
                                               regions as well as ICH folder structure specifications.EMEA should consider
                                               removing the additional util folder from eu folder under m1. All necessary
                                               files (DTD and style sheet) should be placed in their respective folders under
                                               one UTIL folder.Also, note that the relative path in the XML file should be
                                               updated for both DTD and style sheet. See Page 30 onwards.Correct path
                                               is:../../util/dtd/eu-regional.dtd../../util/style/eu-regional.xsl.
                                               Suggestion: Keep one global (for both ICH and Regional) Util folder under
                                               submission (sequence) folder. Util dtd - dtd files for ICH and regional style
                                               – stylesheet for ICH and Regional




0007   IABG (T.         eCTD EU Module 1       eCTD should take into consideration the ISO standard ISO/PRF 19005-1 (           This was referred to ICH where it was         Rejected              None
       Bergsteiner)     Specification          PDF/A) for long-term readibility of PDF documents.                               concluded that PDF/A does not support the
                                                                                                                                review process for eCTDs. Response issued
                                                                                                                                as ICH eCTD Q&A 47.

0008   Spanish Agency   eCTD EU Module 1       EU Module 1 Specification:                                                                                                     Implemented in EU     Dec 05: Implemented in
       of Medicines     Specification          Element : m1-6-1-non-gmo                                                                                                       M1 v1.1               eCTD Spec v1.1, cell 43
       (José Manuel                            Directory : m1/eu/16-environrisk/161-nongmo                                                                                                          p.21
       Vidal Morales)                          eCTD EU Backbone DTD - 1.0:
                                               Element : m1-6-1-non-gmo
                                               Directory : m1/eu/16-environrisk/161-non-gmo (without last hyphen)

                                               In the file eCTD EU Backbone DTD - 1.0 the directory must be named:
                                               m1/eu/16-environrisk/161-nongmo
                                                                      EU eCTD Specification Change Requests
 #       Requestor          Specification                                       Description                                                         Comments                       Status              Action                       Group Where Action
                             Component                                                                                                                                                                                              is Sitting
0009   GSK (Andrew       EU DTD v1.0,          The New Medicines Legislation defines a new procedure for regulatory                Update the attribute values in the DTDs.        Implemented in EU   Dec 05: Implemented in
       Marr)             Specification v1.0,   approval in Europe, that of the Decentralised Procedure. In the current                                                             M1 v1.1             eCTD Spec v1.1 new
                         EAF v1.0              eCTD envelope a picklist provides for the option of Centralised, Mutual                                                                                 attribute in envelope.
                                               Recognition or National. Decentralised needs to be added as an option.
                                               Likewise for the Electronic Application Form. These need to be in place for
                                               adoption of the new procedure in November 2005.


0010   EMEA (J. Rueda) eCTD EU Module 1        The inclusion of the PIM DES into EU Module 1 of the eCTD is planned, as            An additional element “m1-3-1-pim-xxxx-y”       Implemented in EU   Dec 05: Implemented in
                       Specification           per the road map (DES 2.1), for December 2005.                                      will need to be created in EU M1 for            M1 v1.1             eCTD Spec v1.1 - new
                                               This means that the current DES container will need to be re-design in order        accommodating the new PIM container when                            element in 1.3.1
                                               to have a unique container for submitting PIM in/outside eCTD and to                submitted within the eCTD
                                               minimise as much as possible changes in the current eCTD EU Module 1
                                               specifications.
                                               To achieve this, the DES group has proposal for implementation.Currently,
                                               when PIM is submitted inside eCTD, EU M1 has two util folders, one in EU
                                               M1 level and another one at the root level.
                                               The PIM DES container has an util folder as well. The new PIM container,
                                               scheduled for DES 2.1 DEC 05 will align with EU m1 structure (in/outside
                                               eCTD). With this new container there will be a unique "util" folder in EU M1,
                                               the one already in there.
                                               Note that the eCTD specifications define the location for DTDs and style-
                                               sheets.
                                               EU M1 specifications only contain screenshots with “util\dtd” and “util\style”.
                                               Full proposal in Change Request proposal




0011   EMEA (J. Rueda)   eCTD Specification    eCTD requires a two way communication mechanism to allow flexibility and            Referred to ICH - Out of Scope for EU. ICH      Deferred            Referred to ICH for next     ICH M2
                         v3.2                  system interoperability (EURS/PIM RS) for regulators for them to make PIM           will consider for the scope of the next major                       major version of the eCTD.
                                               submissions to applicants either with or without eCTD.                              release (ICH Change Request #1110)
                                                                                                                                                                                                       To be carried forward into
                                                                                                                                                                                                       eCTD Next Major Version
0012   EMEA (J. Rueda)   eCTD EU Module 1      The list of submission types accepted in eCTD format listed in the eCTD             EMEA to prepare a list to be confirmed at the   Duplicated          None
                         Specification         specification should be in line with the list of submission types listed as         eCTD interlinking.
                                               accepted in NtA Volume 2. Currently, the 2 lists are not consistent with one        Nov 2007 - still under consideration and now
                                               another.                                                                            linked to additional CRs - QA-20070906-01 &
                                                                                                                                   CR-20070926-01

0013   EFPIA (A. P. Marr) eCTD EU Module 1     The structure of folders given in the EU Module 1 have „Centralised‟, „Mutual‟      The folder structures should be clarified and   Implemented in EU   Dec 05: Implemented in
                          Specification        and „national‟ as folders between the root folder and the sequence number.          the „procedure‟ folders deleted. This should    M1 v1.1             eCTD Spec v1.1
                                               This was not intended as part of the structure submitted in the eCTD.               improve the clarity of the specification and
                                               Three representative folder structures are provided in the specification to         hence valid submissions.
                                               represent how folders and files should be placed for each of the centralised,
                                               mutual and national procedures. The folder structure includes „centralised‟,
                                               „mutual‟ or „national‟. I do not believe that it was the intent that this folder,
                                               placed between the root directory and the sequence number was intended
                                               to be used in the submission itself. Recently, Belgium has issued guidance
                                               for e-submission and refers to the EU specification but they have been
                                               receiving examples where the applicants have interpreted that the folder
                                               should be included. This will cause problems later when eCTD are received
                                               (rather than just e-subs in folder structures‟
                                                                     EU eCTD Specification Change Requests
 #       Requestor          Specification                                     Description                                                        Comments                        Status                Action                       Group Where Action
                             Component                                                                                                                                                                                              is Sitting
0014   EFPIA (A. P. Marr) eCTD EU Module 1   The newly agreed ICH Q&A #38 on referring to files submitted in previous           ICH Answer :At this stage of the                     Answered in Q&A   Answered as Question #14
                          Specification      sequences indicates that we should refer to regional guidance with respect         implementation of the eCTD, the four
                                             to allowance of cross-referral. This guidance needs to be established.             Operation Attributes (new, append, replace                             Referred to ICH for next
                                             ICH Question: The eCTD specification supports the ability to refer to a            and delete) will remain and not be added to.                           major version of the eCTD.
                                             previously submitted file, for example, by including in sequence 0005 a leaf       With the existing specification it is technically
                                             with Operation Attribute of 'new' that refers to a file submitted in 0000. Is it   possible to determine that a file is not in the
                                             possible to indicate to the reviewer that they have already received and           current sequence, but is from a previous
                                             reviewed the file before? Could an additional Operation Attribute be               sequence.Suppliers of eCTD viewing tools are
                                             considered for this type of cross-referenceing or re-use?                          encouraged to develop a visual way of
                                                                                                                                displaying the difference between a leaf
                                                                                                                                referring to a file in the current sequence and
                                                                                                                                a leaf referring to a file in a previous
                                                                                                                                sequence.In this circumstance note that the
                                                                                                                                list of items to be checked under Q&A No. 36
                                                                                                                                should allow for the xlink:href to refer to files in
                                                                                                                                another sequence and not prevent viewing of
                                                                                                                                the eCTD by another applicant/regulator.Refer
                                                                                                                                to regional guidance with respect to the
                                                                                                                                allowance of reference to previously submitted
                                                                                                                                files.

                                                                                                                                NB. For Europe, this Guidance has been
                                                                                                                                agreed and issued as Q&A #14.

                                                                                                                                Recommendation to update the attribute
                                                                                                                                values in the DTD at a future point



0015   PIM Core Team    eCTD EU Module 1     In December 2005, a CR was requested to include PIM into the EU Module             Recommended solution                             Implemented in EU     Oct 06: Implemented in
                        Specification        1. This CR requested the following actions:                                        - Add TGZ as allowed file format (this format is M1 v1.2.1             eCTD Spec v1.2.1
                                             - Creation of element “m1-3-1-pim” to link to the PIM XML file- Identify the       preferred as it is more open than the ZIP
                                             “util” folder of the EU Module 1 as the appropriate location for PIM utilities     format)
                                             (DTD and style-sheets)                                                             - Add ZIP as allowed file format
                                             - Amend file formats supported by the EU Module 1 to add XML as well as            - Add name specification “131-pim-xxxx-
                                             the image formats (JPEG, GIF, PNG, TIF, SVG, MathML)                               ar.zip/tgz ” for the PIM file
                                             Today, PIM systems are under elaboration and practical experience                  - Keep Element “m1-3-1-pim”
                                             provided some feedback about the way PIM has been integrated into the EU           - Remove description the use of EU M1 “util”
                                             Module 1.                                                                          folder for PIM
                                             Following the feedback received, we believe that there is a simpler way to         - Remove definition of folder “131-pim-xxxx-ar ”
                                             include PIM in EU Module1.
                                             It is more appropriate to include PIM into the EU Module 1 as a single             Refer to PIM DES specifications for
                                             archive file than directly refer to the XML file. Therefore, it is proposed to:    compression protocols
                                             - Add ZIP format and TGZ format as valid file formats
                                             - Remove the need to merge “util” folders for PIM and EU Module 1, as the
                                             PIM util folder will be stored within the ZIP / TGZ file
                                             - Folder “131-pim-xxxx-ar” is no longer needed because PIM will be reduced
                                             to a single file. The name of that file will be
                                             “131-pim-xxxx-ar.zip ” or “131-pim-xxxx-ar.tgz ” depending on the
                                             format used
                                             Further information included in the original change request.
                                                                                EU eCTD Specification Change Requests
    #            Requestor         Specification                                         Description                                                     Comments                        Status              Action                           Group Where Action
                                    Component                                                                                                                                                                                                 is Sitting
   0016       PIM Core Team     eCTD EU Module 1         The link from EU Module 1 to PIM is defined in v1.1 by using the leaf entity                                                    Implemented in EU   Oct 06: Implemented in
                                Specification            as defined by ICH in the context of eCTD. The leaf entity is defined by:                                                        M1 v1.2.1           eCTD Spec v1.2.1
                                                         - Leaf elements
                                                         - Node extension elements (which may contain other leaf and/or node
                                                         extension elements)

                                                         In the context of a PIM submission, only one PIM file needs to be attached
                                                         to the EU Module 1. Also, no concept of node extension is needed.
                                                         Therefore, the EU M1 Specification and DTD need to be updated to define
                                                         element “m1-3-1-pim ” so that it can contain only 1 leaf element

                                                         Recommended Solution:

                                                         Update Specifications and DTD to define element “m1-3-1-pim” containing a
                                                         single leaf element



   0017       Bernadette Billet eCTD EU Module 1         When providing PIM and/or the XML Electronic application form, the EU          They do not have to referece.                    Implemented in EU   Implemented in EU Module
              Liquent, Thomson Specification             Module 1 eCTD version 1.1 specification indicates that the corresponding       Check guidance is clear                          M1 v1.2.1           1 eCTD v1.2.1
              Scientific                                 DTDs and stylesheets should be located in the m1\eu\util directory. Should
                                                         the DTDs and stylesheets also be referenced by <leaf> elements within the
                                                         eu-regional.xml file, or is this unnecessary as simply serve to support the
                                                         XML content of PIM and/or the application form?


   0018       Alex Yates        eCTD EU Module 1         Please can you inform us as to the date when the updated European              Addressed by EU M1 v1.3 specification and        Closed              None
              Kendle            Specification and type   Module 1 specifications issued in January 2006 become mandatory for use        transition plan
                                definition               in all eCTD submissions in the EU. It takes some time to update the system
                                                         for generating the EU Module 1 XML and so this information would be
                                                         useful. In the future, consideration should be given to adding a date for
                                                         coming in to operation to the European Module 1 specifications guideline.


20060524-01   Ron de Boer                                If I submit sequence number 0001. What will be the operation attribute for                                                      Implemented in EU   Implement in v1.3:
                                                         the eu-regional.xml in the index.xml?                                                                                           M1 v1.3             Include a clarification in the
                                                         This can not be replace, because the eu-regional.xml only contains the                                                                              spec in Appendix row 2 -
                                                         updated parts and a replace operation will make all previously submitted                                                                            operation attribute should
                                                         documents obsolete. It is also not new, because the eu-regional.xml has                                                                             be 'new'. Investigate other
                                                         been submitted before. Should it perhaps be append?                                                                                                 locations where an update
                                                                                                                                                                                                             could be provided.


20060627-01   Geoff Williams,   EU Module 1 DTD and Version 1.1 of the EU Module 1 DTD included country and language codes              EU M1 is 1st priority – Lang/country codes for   Implemented in EU   Implemented in EU Module
              Roche             Specification, v1.2 for the planned accession of Romania and Bulgaria. Version 1.2 of the DTD           RO BU in DTD, specifications and style-sheet.    M1 v1.2.1           1 eCTD v1.2.1
                                                    included several changes, including the removal of these country and                Assessment of required changes to align
                                                    language codes. Given the planned accession date of 1st Jan 2007, we                same requirement in eAF-New eAF-Var.
                                                    believe that these codes should be in place now to allow use of the eCTD            EMEA Regulatory Affairs to agree to this CR.
                                                    specification for submissions beginning on January 1st 2007.

                                                         Reinstate the country codes into the DTD. Issue an updated specification
                                                         document (or alternate form of guidance) stating that these codes are not to
                                                         be used in any submission before the formal accession date of these two
                                                         countries to the EU. On the accession date, issue a revision to the
                                                         specification (or other guidance note) allowing the use of the country and
                                                         language codes.
                                                                                   EU eCTD Specification Change Requests
      #             Requestor            Specification                                      Description                                                       Comments                       Status                Action                     Group Where Action
                                          Component                                                                                                                                                                                           is Sitting
 20060627-02     Bernadette Billet,   EU Module 1 DTD and When migrating the product information from Word to PIM for a product              Updated in guidance - Word not to be            Closed                None
                 Liquent              Specification, v1.2 managed by an eCTD how should the operations attributes be used?                   included in the eCTD in any case.

                                                            Version 1.2 DTD allows either a PIM submission or the Word documents in
                                                            1.3.1, not both. For a product that has previously submitted Word PI
                                                            documents these will be located under 131-spc-label-pl but with PIM it will go
                                                            under 131-pim. As such it is not appropriate to use „replace‟ since replace
                                                            should only be used on documents at the same location in the backbone. If
                                                            „new‟ is used for PIM this will still leave the previous Word documents as
                                                            being current. It is not possible to use delete either since the specification
                                                            does not support entry of leafs in both 131-pim and 131-spc-label-pl in the
                                                            same submission. Could guidance please be given for how to manage this
                                                            transition so that the PIM information is seen as new and the old Word
                                                            information is seen simultaneously as „not current‟ when a current or
                                                            cumulative view is used?



 20060627-03     Andrew Marr, GSK EU Module 1 DTD and When to submit Module 3 updates as part of responses to questions with an 16-12-2008 eCTD Interlinking: The module 3                   Accepted - refer to   Produce an NTA CTD Q&A Interlinking
                                  Specification, v1.2 eCTD                                                                         documents should be handled in the same                   Interlinking Group    detailing the guidance to
                                                                                                                                   way that the SPC is currently handled in eCTD                                   submit only the final agreed
                                                      Currently with a paper submission there is the possibility of submitting a   - only the final agreed versions of the                                         version of the M3
                                                      response to a question which may contain a proposal (e.g. a change to the    documents should be submitted at (or just                                       documents in the eCTD.
                                                      specification) and when that is found to be acceptable by the regulators the before) the end of the procedure. The interim                                   (This will set a precedent
                                                      revised Module 3 content can be submitted. With an eCTD is it always         versions should not be exchanged in the                                         for an eCTD Q&A and any
                                                      expected that the Module 3 section is updated at the time of submitting the  eCTD - they should be exchanged as                                              appropriate guidance
                                                      response or can this also be delayed until it is known that the response is  communications outside the eCTD.                                                change).
                                                      acceptable?                                                                  March-09 : Options for Q&A have been
                                                                                                                                   drafted and are to be reviewed by the
                                                                                                                                   Interlinking Group.
 20060703-01     Geoff Williams,  EU Module 1 DTD and                                                                                                                                        Implemented in EU     Implemented in EU Module
                 Roche            Specification, v1.2 The European Commission website URL is incorrect                                                                                       M1 v1.2.1             1 eCTD v1.2.1

                                                            The Commission website is referenced on pages 2, 4 and 7 of Version 1.2
                                                            of the specification. The website URL is incorrect. It should be
                                                            http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm
 20060703-02     Geoff Williams,      EU Module 1 DTD and                                                                                                                                    Implemented in EU     Implemented in EU Module
                 Roche                Specification, v1.2                                                                                                                                    M1 v1.2.1             1 eCTD v1.2.1
                                                            The example filenames given for two documents in the specification are
                                                            incorrect as they include invalid characters (full stops). On page 26 of the
                                                            specification, in the list of the Directory/File Structure for Module 1, the
                                                            entries for items 67 and 69 on the list are invalid.

                                                            In row 67, the file path and filename is proposed as m1/eu/18-
                                                            pharmacovigilance/ 181-phvig-system/phvigsystem.VAR.EXT but it should
                                                            include a hyphen rather than a full stop before the VAR variable, e.g.
                                                            m1/eu/18-pharmacovigilance/ 181-phvig-system/phvigsystem-VAR.EXT

                                                            Likewise, on row 69 the proposed file path and filename is m1/eu/18-
                                                            pharmacovigilance/ 182-riskmgt-system/riskmgtsystem.VAR.EXT but it
                                                            should include a hyphen rather than a full stop before the VAR variable, e.g.
                                                            m1/eu/18-pharmacovigilance/ 182-riskmgt-system/riskmgtsystem-VAR.EXT
 20060914-01     Aziz Diop,           eAF DTD and style     It is mandatory in the DTD to choose an option in the centralised procedure                                                      Deferred              Refer to eAF project       eAF
                 AFSSAPS              sheet                 between (mandatory scope, optional scope and Generic of a Centrally
                                                            Authorised Medicinal Product). Example of a product
                                                            “Aluvia film-coated tablets”
                                                            200mg of lopinavir/50mg of rotonavir
                                                            A CHMP scientific opinion : Article 58 Regulation (EC) N° 726/2004
                                                            Date acceptance by WHO : 24-05-2006
QA-20061017-01   Hans van        ICH eCTD specs v3.2        Nine Questions on the use of the eCTD in Module 3 of the CTD were                This CR/Q&A was submitted to the ICH M2         Closed                Discussed at ICH M2, see
                 Bruggen,        Appendix 6                 submitted.                                                                       group for consideration. It has been added                            ICH tracking sheet for
                 eCTDConsultancy                                                                                                             here for completeness and to record any                               details of outcome.
                                                                                                                                             discussion and position taken at an EU level.
                                                                                   EU eCTD Specification Change Requests
      #             Requestor           Specification                                       Description                                                       Comments                        Status              Action                          Group Where Action
                                         Component                                                                                                                                                                                                is Sitting
QA-20061120-01   Alastair Nixon,                            When submitting via the centralised procedure, changes are frequently            Nov-07 Part i) Accepted for Q&A                 Answered in Q&A      Answered as Question #15
                 GSK                                        required to the dossier following validation by the EMEA. At present, the        Part ii) was referred to eCTD Interlinking
                                                            rapporteur and co-rapporteur have at this stage already received an initial      group, they responded "It is required to submit
                                                            copy of the eCTD.                                                                the application to Rap / Co-Rap at the same
                                                            (i) How is the applicant advised to handle validation changes in the eCTD?       time as to the EMEA. It is therefore not
                                                            Should another eCTD sequence be created, incorporating the suggested             possible to submit to Rap / Co-Rap only after
                                                            changes, or should the original sequence be corrected? NB If an additional       validation of the application."
                                                            sequence were to be provided, the assessor would need to view both
                                                            sequences in „current‟ view in an eCTD viewer. Further, if the original
                                                            submission was not 0000, in some eCTD viewing tools, it is currently not
                                                            possible to view the „current‟ content of selected sequences only – the tool
                                                            will only allow the user to view the current view of all submitted sequences.
                                                            (ii) What is the EMEA‟s view on provision of copies of the electronic dossier
                                                            for the rapporteur and co-rapporteur? Could this be delayed until after
                                                            validation, to prevent industry having to submit either updated original
                                                            sequence or 2 sequences?


CR-20061120-02   Shy Kumar,         eCTD EU Module 1        The example submission directory structure for MRP (Appendix 3) may be Mar-07 After discussion, it was agreed that                Duplicated          None
                 Datafarm           specification v1.2.1    inconsistent with the accompanying statement that „common‟ is the directory the examples are correct and do not require
                                                            to hold all files applicable to more than one country                       changing.

CR-20061221-01   Kevin Wing,        eCTD EU Module 1        EU Module 1 Specification v1.2.1 (and predecessors) requests that the            Sep-07 Proposed for Q&A                          Implemented in EU   Implement in v1.3:
                 J&JPRD             specification v1.2.1,   variable component of filenames should be a “meaningful concatenation of                                                          M1 v1.3             Answered as Q&A #16.
                                    page 7                  words without separation and should be kept as brief and descriptive as                                                                               Change p.7 of the
                                                            possible” but also specifies that hyphens (“-“) should not be used within                                                                             specification 'file naming
                                                            these variable components. The change request applied for is to allow the                                                                             convention'
                                                            use of hyphens within the variable component of filenames in the EU
                                                            Module 1.




CR-20070118-01   Harv Martens, ING eCTD EU Module 1         Examples 2 and 3 of the EU Module 1, in the context of v1.2.1, are incorrect Mar-07 Accepted to update example files              Implemented in EU   Implement in v1.3:
                 America           specification v1.2.1,    regarding the Specifications.                                                                                                     M1 v1.3             Change as specified
                                   examples                 EU M1 Specifications require PI documents (section 1.3.1) to be named as
                                                            follows:
                                                            CC/LL/CC-SPCDOC-VAR.EXT
                                                            For instance, a French SPC in Belgium should be named, e.g.:
                                                            be/fr/be-spc.doc
                                                            Examples 2 and 3 name such file with the prefix set to the language instead
                                                            of the country: be/fr/fr-spc.doc
                                                            Examples need to be updated so that the name of the PI documents is inline
                                                            with the EU M1 Specifications.
CR-20070122-01   Harv Martens, ING eCTD EU Module 1         Examples 2 to 4 contain a util folder within the m1/eu folder. This folder can   Mar-07 Examples to be corrected, and to          Implemented in EU   Implement in v1.3:
                 America           specification v1.2.1,    exist to hold EU-specific files (DTDs and/or style-sheets) but in the provided   include index.xml and MD5 checksum to            M1 v1.3             Change the 3 examples in
                                   examples                 examples, this folder contains the EU Module 1 DTD files. This is incorrect      reflect valid eCTD submissions.                                      all the locations as detailed
                                                            and can be misleading                                                                                                                                 in the change request itself


CR-20070130-01   Shy Kumar,         eCTD EU Module 1        The EU Module 1 Specifications, version 1.1, provided a description of the        Mar-07 No change to specification. No re-       Rejected            None
                 Datafarm           specification v1.2.1    field "submission-description" in the envelope, including a size limitation set instatement of max. 50 character field length.
                                                            to 50 characters.                                                                 Gain practical experience with no limitation.
                                                            The EU Module 1 Specifications, version 1.2.1, has removed the information
                                                            on the field size limitation. There is no indication whether the limitation still
                                                            applies or not.
                                                            Note: A similar question has been asked in the context of the eCTD on the
                                                            length of the "title" element(Change Request 750). The initial answer was to
                                                            limit the 1024 bytes. However during one of the last meetings (June 2006), it
                                                            has been decided to remove the size limitation, and to request concise titles.
                                                                                    EU eCTD Specification Change Requests
      #             Requestor          Specification                                         Description                                                         Comments                       Status         Action                           Group Where Action
                                        Component                                                                                                                                                                                               is Sitting
CR-20070215-01   Ashley Birch,      ICH eCTD Q&A 40          ICH eCTD Question Number 40 asks whether it is acceptable to submit PDF                                                            Rejected       Discussed at ICH M2, see
                 AstraZeneca                                 V1.4 files across all regions. Although the answer given is in the affirmative,                                                                   ICH tracking sheet for
                                                             it actually goes much further than mere „acceptability‟ by appearing to make                                                                      details of outcome.
                                                             V1.4 mandatory for eCTDs. Shouldn‟t V1.4 be „acceptable‟ or perhaps
                                                             „preferred‟ (if justified) rather than „mandatory‟?



CR-20070309-01   Kevin Wing,        eCTD EU Module 1         Page 39 of EU Module 1 Specification v1.2.1 suggests that the envelope             Sep-07 “Common” should not be an allowable Implemented in EU   Implement in v1.3:
                 J&JPRD             specification v1.2.1     element of MRP or DCP submissions could be assigned a country attribute            value for the envelope.                       M1 v1.3          p.6 section 'Envelope' -
                                                             value "common" when the same sequence is being submitted to multiple               Change wording to specify the use of multiple                  propose text for inclusion
                                                             countries. The change request applied for is to change the example to              country-specific elements.                                     here. Also change example
                                                             illustrate the use of multiple repeated country-specific envelopes, instead of     Write a Q&A to clarify until new version is                    text which illustrates this on
                                                             a single envelope labeled “common”.                                                produced                                                       p.39
                                                                                                                                                                                                               See Q&A #17

                                                                                                                                                                                                               20080220: See CR-
                                                                                                                                                                                                               20080129-02

CR-20070316-01   N. Chandar, Take   ICH Specification v3.2                                                                                                                                      Deferred       Discussed at ICH M2, see         ICH M2
                 Solutions                                                                                                                                                                                     ICH tracking sheet for
                                                             The query relates to details of the Q&A document (MS Excel spreadsheet)
                                                                                                                                                                                                               details of outcome.
                                                             under Question 12. This currently states : Q. The eCTD Specification allows
                                                             for one novel excipient in 3.2.A.3. What happens if there is more than one?
                                                                                                                                                                                                               To be carried forward into
                                                             A. The regulatory authority should be consulted for a solution until the
                                                                                                                                                                                                               eCTD Next Major Version
                                                             change request is resolved.

                                                             Change Request 00050 stated : Description :Request 3.2.A.3 to be
                                                             changed to a repeating element. Comment : Understood and will address in
                                                             Q&A (No. 12) and then next version of DTD. Status : Approved for
                                                             specification change. Action : Specification changed to Version 3.2

                                                             Specification v3.2 just repeats the same text in dtd ( does not give an
                                                             attribute list to be captured similar to m3-2-a-2).

                                                             Could an attribute for „excipient‟ be introduced and/or a naming convention
                                                             for file naming convention be defined.
CR-20070405-01   Geoff Williams,    ICH Q&A, Q&A36,          ICH Q&A36, item 12 says “Ensure all the files identified by an xlink:href          This CR/Q&A was submitted to the ICH M2         Closed         Discussed at ICH M2, see
                 Roche              item 12                  reference exist”. This should be clarified to state where the files can exist.     group for consideration. It has been added                     ICH tracking sheet for
                                                                                                                                                here for completeness and to record any                        details of outcome.
                                                             The check for item 12 is ambiguous as to where the file identified in              discussion and position taken at an EU level.                  Addressed in EU Q&A 14
                                                             xlink:href should exist. At the time this was written, we probably meant “exist                                                                   as regional guidance
                                                             within the same sequence”. However, current thinking on the use and reuse
                                                             of content means that content can exist in another sequence within the
                                                             same application or (for the US at least) within a separate application Some
                                                             testing of this was carried out in the ETICS study and the results showed
                                                             that tools were not necessarily sticking to the strictest interpretation (within
                                                             the same sequence). This item description should be amended to describe
                                                             the current use and understanding of the xlink:href.



CR-20070405-02   Geoff Williams,    ICH Q&A36, Item 20       ICH Q&A36, item 20 states “Ensure that leaf or node extension Title attribute This CR/Q&A was submitted to the ICH M2              Deferred       Discussed at ICH M2, see         ICH M2
                 Roche                                       is not empty (except when the operation attribute is delete)”. It is not clear    group for consideration. It has been added                      ICH tracking sheet for
                                                             why the parenthetical condition for delete is in place.                           here for completeness and to record any                         details of outcome.
                                                                                                                                               discussion and position taken at an EU level.
                                                             It is not clear why the ICH response should be so proscriptive about the
                                                             content of the title attribute when the leaf is to be deleted. There is value in
                                                             having a title attribute even for leaf elements that will be deleted, so that the
                                                             view of a single sequence has information to aid the user. I propose that the
                                                             condition is removed so that this reads “Ensure that leaf or node extension
                                                             Title attribute is not empty”
                                                                                    EU eCTD Specification Change Requests
      #             Requestor            Specification                                       Description                                                        Comments                       Status              Action                        Group Where Action
                                          Component                                                                                                                                                                                              is Sitting
CR-20070405-03   Geoff Williams,      ICH DTD, v3.2                                                                                            This CR/Q&A was submitted to the ICH M2         Deferred            Discussed at ICH M2, see      ICH M2
                 Roche                                       The approved Change Request 00050 says that the element for Module                group for consideration. It has been added                          ICH tracking sheet for
                                                             3.2.A.3 will be made a repeating attribute in Version 3.2 of the specification.   here for completeness and to record any                             details of outcome.
                                                             This does not appear to have been done.                                           discussion and position taken at an EU level.
                                                                                                                                                                                                                   To be carried forward into
                                                             The change request says that the element for Module 3.2.A.3 (Novel                                                                                    eCTD Next Major Version
                                                             Excipient) will be made a repeating element. This means to me that it
                                                             should be able to appear 0, 1 or more times in the structure. The cardinality
                                                             should be denoted with a * in the element description. However, version 3.2
                                                             is as follows:
                                                             <!ELEMENT m3-2-a-appendices (leaf* , m3-2-a-1-facilities-and-equipment* ,
                                                             m3-2-a-2-adventitiousagents-safety-evaluation* , m3-2-a-3-excipients?)>
                                                             As you can see, the cardinality is indicated by a ? and this means that the
                                                             element can appear 0 or 1 times only. This change needs to be
                                                             implemented in v3.3.1 to allow further change requests about this element to
                                                             be considered.
CR-20070408-01   Dirk Beth, Mission ICH DTD, v3.2            Mission3 submits this change request with the suggestion of migrating the         This CR/Q&A was submitted to the ICH M2         Deferred            Discussed at ICH M2, see      ICH M2
                 3                                           narrative content of submissions from PDF to XML. An XML model that fits          group for consideration. It has been added                          ICH tracking sheet for
                                                             the needs of this industry will yield significant benefits to both sponsors and   here for completeness and to record any                             details of outcome.
                                                             regulatory reviewers.                                                             discussion and position taken at an EU level.                       Part of Workplan for ICH
                                                                                                                                                                                                                   M2 SENTRI group to
                                                                                                                                                                                                                   consider
CR-20070426-01   Joe Cipollina, BMS ich-stf-stylesheet-2-    The ICH STF Stylesheet currently posted gives inconsistent display results        This CR/Q&A was submitted to the ICH M2         Closed              Discussed at ICH M2, see
                                    2.xsl                    in Internet Explorer. It seems to work in some cases but not in others. STF       group for consideration. It has been added                          ICH tracking sheet for
                                                             files which were viewable with the older version of the stylesheet are no         here for completeness and to record any                             details of outcome.
                                                             longer always viewable.                                                           discussion and position taken at an EU level.
CR-20070426-02   Joe Cipollina, BMS Valid-values.xml         There are differences in the values listed in the valid-values file posted on     This CR/Q&A was submitted to the ICH M2         Closed              Discussed at ICH M2, see
                                                             the ESTRI website and the valid-values file posted on the FDA website.            group for consideration. It has been added                          ICH tracking sheet for
                                                                                                                                               here for completeness and to record any                             details of outcome.
                                                                                                                                               discussion and position taken at an EU level.
QA-20070627-01   Alastair Nixon,                             One principle of the eCTD is that content that is not required for the dossier Nov-07 Q&A wording proposed                        Implemented in EU   Implement in v1.3:
                 GSK                                         is not provided, and there is no need for the applicant to provide „not                                                           M1 v1.3             Answered asQ&A #18.
                                                             applicable‟ pages. However, we have experienced occasions where we                                                                                    Change text on p.6 to
                                                             receive questions after EMEA content validation with respect to sections that                                                                         include text from Q&A 18.
                                                             are missing in the eCTD, but where no justification has been provided.                                                                                Add a statement to indicate
                                                             Is it necessary to include statements in the CTD/eCTD justifying the absence                                                                          that further information
                                                             of data? If so, where should these statements be placed in the CTD                                                                                    national guidance should
                                                             structure?                                                                                                                                            be referred to.
                                                             Further information included in the original change request


CR-20070627-01   Alastair Nixon,      eCTD EU Module 1       Error in Appendix 2, suggesting that applicant uses the 10-cover section for      Sep-07 Accepted for next release of             Implemented in EU   Implement in v1.3:
                 GSK                  specification v1.2.1   response to questions                                                             specification                                   M1 v1.3             Remove reference in row 5,
                                                                                                                                                                                                                   appendix 2, p.13
QA-20070628-01   Thierry Le Ridant,   eCTD EU Module 1       During a sequence 0026, we must modified SPC of the 0020 sequence and             Nov-07 Both proposals are considered            Answered in Q&A     Answered as Q&A #12
                 Ethypharm            specification v1.2.1   leaflet of the 0022 sequence.                                                     incorrect. A Q&A has been drafted to clarify
                                                             What should be the value of the <related-sequence> in the <envelope>?             use of related-sequence attribute
                                                             The last sequence modified (0022) or it should be blank?                          See also CR A012
                                                                                                                                               See Question 12

QA-20070628-02   Thierry Le Ridant,   eCTD EU Module 1       Is it possible to have a list of value for the <agency-name> in order to          Nov-07 EMEA has referred to EUTCT group         Implemented in EU   Implement in v1.3 if values
                 Ethypharm            specification v1.2.1   standardised the value of this element.                                           to define list                                  M1 v1.3             list exists:

                                                                                                                                                                                                                   20080220: List to be
                                                                                                                                                                                                                   implemented in EUTCT - to
                                                                                                                                                                                                                   come from ECD


QA-20070628-03   Thierry Le Ridant,                          For an association of two active substance (eg Paracetamol /                      Sep-07 Requested to be withdrawn and            Withdrawn           None
                 Ethypharm                                   dextroproxifen), what is the best practice : duplicate <atc> and <inn>            resubmitted as a CR (subsequently submitted
                                                             element ?                                                                         as CR-20070718-01)
                                                                                    EU eCTD Specification Change Requests
      #             Requestor            Specification                                       Description                                                        Comments                       Status              Action                        Group Where Action
                                          Component                                                                                                                                                                                              is Sitting
QA-20070628-04   Thierry Le Ridant,   eCTD EU Module 1       DCP or MRP are followed by a national phase (PIL etc.). What should be            Response provided in Best Practice guide for    Closed              None
                 Ethypharm            specification v1.2.1   the value of the "procedure type" field "national" or "MRP" ?                     use of eCTD in MRP/DCP published by
                                                                                                                                               CMD(h).
CR-20070628-01   Thierry Le Ridant,   EU Module 1            Data from the envelope is displayed in blue but they are not hyperlinks. The      Sep-07 Analysis undertaken of all EU            Implemented in EU   Implement in v1.3:
                 Ethypharm            stylesheet             use of blue text should be limited to hyperlinks                                  stylesheets shows inconsistency. Change         M1 v1.3             Stylesheet to be updated to
                                                                                                                                               request accepted and will be implemented in                         include all black text.
                                                                                                                                               next updates of each stylesheet

CR-20070711-01   Alban Dhanani,       eAF-New v2.1           The current Application Form for New applications is not well designed in                                                         Deferred            Refer to eAF project          eAF
                 AFSSAPS                                     terms of reporting of CMS involved in subsequent waves in the case of a
                                                             repeat use in the decentralised procedure. The impact on the current eAF-
                                                             New is even bigger since it is not possible to identify CMS for different
                                                             waves (wave number element missing) and a change to the dtd is needed to
                                                             make it possible.

CR-20070714-01   Kevin Wing,     eAF New specification       The specification for the eAF-new does not specify the use of relative            Sep-07 Accepted for next release of eAF-        Deferred            Refer to eAF project -        eAF
                 eCTDConsultancy                             filepaths for the xlink:href attribute value                                      New specification                                                   Accepted for next minor
                                                                                                                                                                                                                   update of eAF
CR-20070718-01 Thierry Le Ridant,     eCTD EU Module 1       In the Envelope, in the case of an association of 2 active substances, there      Nov-07 Was referred to eCTD Interlinking         Rejected           None
               Ethypharm              specification v1.2.1   is no link between the <inn> element and the <atc> element. We suggest to         Group "No changes required – Because there
                                                             regroup them into an <active> element which will permit to identify the link      is no one to one relationship between
                                                             between atc and inn.                                                              substance and atc codes. The codes relate to
                                                                                                                                               the indication of the product."
                                                                                                                                               Subsequent research shows this may not be
                                                                                                                                               correct.
                                                                                                                                               June 2008: eCTD Interlinking: ATC code left in
                                                                                                                                               EU M1 v1.3
                                                                                                                                               Dec 08: Interlinking Group - there is definitely
                                                                                                                                               no link between the substance and the
                                                                                                                                               atc.Consideration of whether to remove the
                                                                                                                                               atc from the eCTD envelope, in anticipation of
                                                                                                                                               the eAF which will enable use of structured
                                                                                                                                               meta-data on the submission (including the atc
                                                                                                                                               if necessary).
                                                                                                                                               March-09 : Close this change request. Open
                                                                                                                                               new change request for deletion of ATC code
                                                                                                                                               from EU Module 1 specification. Ensure that
                                                                                                                                               requirements for ATC code use are defined
                                                                                                                                               and progressed within eAF project.

QA-20070813-01   Phyllis Thomas,                             In Europe (and with the current ICH M2 eCTD specification), does the              Aug-07 Requested to be withdrawn due to an      Withdrawn           None
                 AstraZeneca                                 applicant need to update attributes in the eCTD backbone during the life an       error. To be resubmitted after correction of
                                                             application?                                                                      error. (Resubmitted as Q&A-20070816-01)
                                                             Further detail included in original question.
CR-20070814-01   Ann Verhoye,         ICH CR 1550            Request to re-open change request 1550: this change request is closed             Sep-07 Examples in two provided annexes         Rejected            None
                 FAMHP, Belgium                              mentioning that all filenames in module 2.3 and 3 will be mentioned in italics:   were reviewed. No consensus on proposal
                                                             this means that no filename check is possible, and no standard for filenames      Rejected
                                                             could be introduced. FAMHP, has made a proposal in order to foresee the
                                                             possibility for multiple documents to be submitted within module 3, so to
                                                             allow granularity, and to keep filename standards as well, therefore, the
                                                             FAMHP requests to reopen this CR and to have a look at the FAMHP
                                                             granularity proposal in order to foresee variable parts in the filenames and to
                                                             maintain fixed components as a standard. First reactions form the national
                                                             IT workgroup in Belgium were very positive.


QA-20070816-01 Phyllis Thomas,                               In Europe (and with the current ICH M2 eCTD specification), does the              Sep-07 Question to be referred to ICH M2        Answered in Q&A     Answered as Question #19
               AstraZeneca                                   applicant need to update attributes in the eCTD backbone during the life an       Q&A.                                                                Refer to ICH Q&A
                                                             application?                                                                      An EU Q&A to be prepared in the interim
                                                             Further detail included in original question.                                     period
                                                                                 EU eCTD Specification Change Requests
      #             Requestor         Specification                                       Description                                                     Comments                       Status              Action                        Group Where Action
                                       Component                                                                                                                                                                                           is Sitting
CR-20070816-01   Kevin Wing,     eAF-New v2.1             The specification for the eAF-new does not enable multiple meeting dates to    Sep-07 Accepted for next update to the          Deferred            Refer to eAF project -        eAF
                 eCTDConsultancy                          be included for provision of CHMP scientific advice (section 3.1) or for       specification                                                       Accepted for next minor
                                                          Member State scientific recommendations (section 3.2)                                                                                              update of eAF
QA-20070906-01 Hans van        eCTD EU Module 1           Could the TIGes clarify what <Submission> “type” attribute value should be     Nov-07 Review required across other             Implemented in EU   Implement in v1.3:
               Bruggen,        specification v1.2.1       selected for the following types of submission:                                specifications. See also CR-20070926-01         M1 v1.3             Propose revised list. See
               eCTDConsultancy                            1. Annual Reassessment                                                                                                                             CR-20070926-0 - ensure
               B.V.                                       2. Duplex registration                                                                                                                             these values are in the
                                                          3. Line Extension                                                                                                                                  revised list. Also include
                                                                                                                                                                                                             community referrals.


CR-20070906-01   Reinko Abels,     eCTD EU Module 1       The current EU Module 1 specification does not specify that content files in   Nov-07 Accepted with proposed change to         Implemented in EU   Implement in v1.3:
                 Qdossier B.V.     specification v1.2.1   the ICH section can be pointed to by eCTD leaf elements in the eu-             wording to page 6 of the specification.         M1 v1.3             Include a short additional
                                                          regional.xml file                                                              See also CR-20070927-01                                             section on p.6 under
                                                                                                                                                                                                             'General Architecture'.
                                                                                                                                                                                                             Wording to clarify that
                                                                                                                                                                                                             content filesin the ICH
                                                                                                                                                                                                             section can be pointed to
                                                                                                                                                                                                             from regional leaf elements
                                                                                                                                                                                                             (see CR-20070927-01)
                                                                                                                                                                                                             See Q&A #21


CR-20070912-01   Jose Manuel       eAF-New v2.1           Orphan medicinal product information (section 1.2) applies to all types of                                                     Deferred            Referred to eAF project for   eAF
                 Simarro, AEMPS,                          procedures not only for centralised ones.                                                                                                          resolution
                 Spain
CR-20070926-01   Juan Rueda        eCTD EU Module 1       Update Specifications re list of procedure types                               Nov-07 Review required across other             Implemented in EU   Implement in v1.3:
                 Montes, EMEA      specification v1.2.1                                                                                  specifications. See also QA-20070906-01         M1 v1.3             List should be finalised:
                                                                                                                                                                                                             Propose final list for
                                                                                                                                                                                                             agreement by NtA
                                                                                                                                                                                                             Interlinking/TIGes


CR-20070927-01   Ulrika Lantz,     eCTD EU Module 1       Many post-approval submission types require a copy of an already approved      Nov-07 The eCTD specification already           Implemented in EU   Implement in v1.3:
                 AstraZeneca       specification v1.2.1   specification to be submitted. The basis for eCTD is to submit documents       defines how to reference content from more      M1 v1.3             Include a short additional
                                   and Guidance on Type   only once, but to be able to fulfil the European variation guidelines all      than one leaf location. Some clarity might be                       section on p.6 under
                                   1A and 1B variations   required documents would need to be submitted. This change request gives       added to specification.                                             'General Architecture'.
                                                          a suggestion on how this could be handled in eCTD.                             See also CR 20070906-01                                             Wording to clarify that
                                                          Further information included in the original change request.                                                                                       content filesin the ICH
                                                                                                                                                                                                             section can be pointed to
                                                                                                                                                                                                             from regional leaf elements
                                                                                                                                                                                                             (see CR-20070906-01)
                                                                                                                                                                                                             See Q&A #21

CR-20070928-01   Leo van de        Notice to Applicants   The ASMF guidelines state that the manufacturer and the applicant should       Nov-07 This issue is referrd to the NtA Q&A     Deferred            Subgroup of Interlinking   Interlinking
                 Winkel, N.V.      vol 2B                 both submit an identical Applicant‟s Part (AP) of the EDMF.                    on handling of ASMF                                                 group to be established to
                 Organon                                  Guidelines for eCTD files indicate that the AP should be included in Section   March-09 : Subgroup of Interlinking group to                        produce guidance for ASMF
                                                          3.2.S of the eCTD.                                                             be established to produce guidance for ASMF
                                                          Section 3.2.S does not allow the AP to be included as one document; the
                                                          AP should be separated in parts reflecting the CTD structure and the
                                                          general parts of the AP can not be included in 3.2.S.
                                                          Conclusion: if the AP of the EDMF is included in part 3.2.S than it is not
                                                          identical anymore to the AP submitted by the ASMF.
                                                          Further information included in the original change request
CR-20071001-01   Deanna Murden,                           How should sponsors manage summary documents in Module 2 over the              Nov-07 Referred to ad hoc group for             Deferred            Referred to Harmonisation     Harmonisation
                 i3Logic                                  lifecycle of an application?                                                   discussion and position                                             Tasforce
                                                                                 EU eCTD Specification Change Requests
      #             Requestor         Specification                                       Description                                                        Comments                         Status              Action                         Group Where Action
                                       Component                                                                                                                                                                                                 is Sitting
CR-20071002-01   Juan Rueda        eCTD EU Module 1       Should eCTD Module 1 section "additional data" be empty for EMEA                  Feb 08: Specify in EU M1 v1.3 that this           Implemented in EU   Answered as Question 20
                 Montes, EMEA      specification v1.2.1   centralised procedures?                                                           section can be used for CP in a transition        M1 v1.3             Refer to CTD Guidance #4
                                                                                                                                            period for submitting documents as part of a                          on use of the additional
                                                                                                                                            new M1 structure before the latest DTD                                data section (i.e. it should
                                                                                                                                            version is implemented (e.g. paediatrics data).                       not be used for CP) -
                                                                                                                                                                                                                  amend therefore line 68 of
                                                                                                                                                                                                                  the table in appendix 2


CR-20071003-01   Alastair Nixon,   eCTD EU Module 1       Supporting data for variations that is not provided in m3 is currently either     Nov-07 An EU CTD Q&A (4c) already exists          Implemented in EU   Implemented Appendix 2
                 GSK               specification v1.2.1   provided with the cover letter (p13 of EU M1 Specification v121), or as an        about the placement of additional documents       M1 v1.3             row 72.
                                                          annex to the form (p14). It is proposed that all supporting data is provided in   in Variations. Accepted to update EU M1
                                                          the same location, as an annex to the form. In addition, it is proposed that a    eCTD specification in line with CTD Q&A
                                                          table of suggested names is added to the specification, such that these           response.
                                                          documents are provided in a consistent manner.
                                                          Further information included in the original change request


CR-20071009-01   Hans van        eCTD EU Module 1         Guidance is needed on how to maintain the lifecycle of Section 1.6                Nov-07 Referred to ad hoc group for               Deferred            Referred to Harmonisation      Harmonisation
                 Bruggen,        specification v1.2.1     Environmental risk Assessments, using the operations new, append replace          discussion and position                                               Tasforce
                 eCTDConsultancy                          and/or delete.
                 B.V.                                     Further information included in the original change request

QA-20071022-01   Alastair Nixon,                          In the eCTD, how should an applicant handle multiple variations that occur        Nov-07 Best Practice guide written for review Accepted - refer to     Present guidance for          Interlinking
                 GSK                                      in parallel and affect the same document?                                         and approval                                    Interlinking Group    consideration by Interlinking
                                                                                                                                            March-09 : Subgroup to be established to
                                                                                                                                            address all issues of variation, in the context
                                                                                                                                            of the new Variations Regulations. This CR will
                                                                                                                                            be addressed within this group.




CR-20080129-01   Geoff Williams,   EU M1 stylesheet       The current stylesheet displays the full structure of the Module 1, whether                                                         Rejected            None
                 Roche                                    the displayed sections have content or not. This is a little confusing as it
                                                          gives the impression of much more information than is really present. In
                                                          addition, some sections are mutually exclusive and others only apply for
                                                          particular procedure types.
                                                          The display of the complete structure is not consistent with the behaviour of
                                                          the ICH stylesheet, which only displays sections that have content.
                                                          Proposal: Change the stylesheet so that it only displays sections that have
                                                          content.
                                                                                   EU eCTD Specification Change Requests
      #             Requestor          Specification                                         Description                                                        Comments                        Status              Action                      Group Where Action
                                        Component                                                                                                                                                                                               is Sitting
CR-20080129-02   Geoff Williams,    EU Module 1 DTD, eu- A previously submitted CR (20070309-01) proposed the prohibition against              Feb 08: New change request to be submitted       Withdrawn           None
                 Roche              envelope.mod and      the use of “common” as an acceptable country identifier in the EU Module 1           by EFPIA proposing a 'softened' approach
                                    Specification, v1.2.1 envelope. This CR seeks to clarify the use, or otherwise, of the country             where the country identifier 'common' can be
                                                          identifier “ common” for content files in the EU Module 1.                           used in certain circumstances.

                                                           Currently, no clear guidance exists about the correct use of the country
                                                           identifier “common” when creating an EU Module 1 eCTD, particularly in
                                                           relation to the application of this country identifier to content files. This has
                                                           led to an inconsistency in usage of the value for the country attribute.

                                                           A country identifier is used for content included in sections of Module 1 that
                                                           can contain country specific content. The original intent of the “common”
                                                           country value was to provide some means of identifying content that was
                                                           used submitted in a section that can contain country specific information but,
                                                           in this particular submission, is reused by several countries.

                                                           Propsal:The submitter of this CR proposes completely removing the country
                                                           identifier “common” from the list of acceptable country identifier values.
                                                           Specific guidance should be included about to how to manage content that
                                                           is used in more than one country.




CR-20080129-03   Geoff Williams,    eCTD Specification     ICH eCTD Q&A 46 states “all regions have agreed to accept PDF 1.4.                  Feb 08: New proposal with simpler wording to     Implemented in EU   Implemented on Page 5
                 Roche              v1.2.1                 Please consult regional guidance to submit other versions of PDF.”.                 come from EFPIA, clarifying further the use of   M1 v1.3
                                                           Clarification is required about the acceptability of versions of PDF other than     PDF versions.
                                                           PDF 1.4 in the EU region.                                                           N.B. EU Validation Criteria specify v1.4 (but
                                                                                                                                               warning only).
                                                           It is noted that the planned EU eCTD Validation Criteria will include a
                                                           statement that all files should be PDF 1.4.                                   All PDF files included in the eCTD should be
                                                                                                                                         v1.4 except where there is an agency specific
                                                           However, it is also noted that some specific EU NCAs require the use of       requirement for a later version eg. for an
                                                           Acrobat Forms and other documents created in later versions of PDF and        application form.
                                                           that do not function as needed if created in a lower version of PDF. Specific
                                                           attention is drawn to the MHRA Application Forms that require Acrobat 7.1
                                                           (PDF 1.6) and the EMEA Paediatric Implementation Plan Application Forms
                                                           that require Acrobat 8 (PDF 1.7).

                                                           Proposal: Adoption of the following statement in the EU Module 1
                                                           Specification document.

                                                           PDF files submitted as part of an eCTD must be at least version PDF 1.4.
                                                           Earlier versions of PDF must be converted to at least PDF 1.4. Files created
                                                           with later versions of PDF may be submitted as part of a European eCTD.


 CR-20080218     Andrew Marr, GSK                          The Best Practice for eCTD in MRP/DCP (draft v0.4) includes as             To be included in eCTD v1.3 2008                          Implemented in EU   Implemented in Appendix 2
                                                           requirement to provide a table as a file under 1.0 Cover Letter that keeps                                                           M1 v1.3             Line 4
                                                           track of the sequences, when and when they have been submitted. This will Format and layout of the table to be defined
                                                           allow each NCA to know that any „missing‟ sequences are not relevant to    by eCTD Interlinking Group.
                                                           them and hence have not been submitted. The example tables in the
                                                           guidance have been developed in Word and would be expected to be
                                                           submitted as a PDF. However, when an earlier version of the guidance was
                                                           provided to vendors for comment, several made a request that this table is
                                                           able to be supplied as an xml file as this would allow it to be generated
                                                           automatically by the building tools. Production of a word-processed file
                                                           would be inefficient.

 CR-20080303     Claire Holmes,     EU M1 Specification    The proposed new EU M1 CTD Guidance from NtA includes a new section                                                                  Implemented in EU   Included in DTD and
                 EMEA               v1.2.1                 1.10 Information relating to Paediatrics. The eCTD specification should be                                                           M1 v1.3             througout the document
                                                           updated in line with the new CTD structure.
                                                                                 EU eCTD Specification Change Requests
    #           Requestor           Specification                                         Description                                                      Comments                        Status                Action                         Group Where Action
                                     Component                                                                                                                                                                                                  is Sitting
CR-20080415   Ms Nadine         EU Module 1                As a manufacturer for plasma products, CSL have a centrally authorised         Refer to eCTD Interlinking Group to write        Accepted - refer to   EMEA to draft guidance         Interlinking
              Schwarz           specification,             Plasma Master File (PMF). Following the centralised authorisation of the       interim guidance on which submission type to     eCTD Interlinking
              CSL Behring AG    Appendix 1 "Envelope       PMF the PMF 2nd Step Procedure must be performed. In this 2nd Step             use.                                             Group
                                Element Description",      Procedure, the PMF certificate must be submitted for each product in order     March-09 : Draft guidance is under
                                therein element =          to make the link between PMF and the product's marketing authorisation.        development by EMEA, taking into account
                                submission and             According to the "Guideline on Plasma Master File (PMF) And Vaccine            the new regulations, and will be circulated to
                                attribute = type (p. 10)   Antigen Master File (VAMF) “Second Step”" this is NOT a variation              the Interlinking group for endorsement
                                                           submission.
                                                           If this is done for an existing eCTD, there is no adequate submission type
                                                           defined in the Module 1 Specification to describe this submission.
                                                           Recommendation: Define an additional valid submission type for a PMF 2nd
                                                           Step Submission, such as "pmf-2nd-step".

CR-20080514   Kevin Wing,     EU Module 1                  The example provided for the application number element description on         Refer to eCTD Interlinking Group for             Open                  Complete the survey for    TIGes
              eCTDConsultancy Specification v1.2.1         page 9 of the guidance is in the format of an EMEA Marketing Authorisation     discussion and drafting of Q&A on what is                              MS on requirements for
                                                           Number i.e. EU/1/00/150/001 and not an EMEA Procedure Number such as           expected in that field. Draft survey for MS on                         application/procedure
                                                           EMEA/H/C/XXX/X/XX.                                                             requirements for application/procedure                                 number, and use of this
                                                                                                                                          number, and use of this element.                                       element. Once results have
                                                           The accompanying description that this is the “number assigned to the                                                                                 been gathered, produce a
                                                           application by the receiving agency” suggests that what is meant here is the                                                                          new change request as
                                                           procedure number, and not the marketing authorization number (which                                                                                   appropriate requesting a
                                                           would only be assigned upon approval and would also be strength-specific).                                                                            change to the way
                                                           This is supported by the explanation provided on page 14 of the EMEA‟s                                                                                application numbers are
                                                           recently released Q&A on eCTD Implementation (7th February 2008).                                                                                     captured in the envelope.
                                                           Change the example for the application number element from:                                                                                           Based on the technical
                                                           EU/1/00/150/001                                                                                                                                       guidance given in the new
                                                           to                                                                                                                                                    eCTD specification,
                                                           EMEA/H/C/XXX/X/XX.                                                                                                                                    produce associated
                                                           And add a clarification to the description that the number required for this                                                                          business guidance on how
                                                           value is the procedure number.                                                                                                                        each application number
                                                                                                                                                                                                                 element is to be used. (KM
                                                                                                                                                                                                                 to complete survey and
                                                                                                                                                                                                                 submit CR as appropriate
                                                                                                                                                                                                                 in collaboration with
                                                                                                                                                                                                                 industry)

                                                                                                                                                                                                                 Produce interim guidance
                                                                                                                                                                                                                 relating to current EU M1
                                                                                                                                                                                                                 specification and the use of
                                                                                                                                                                                                                 application numbers,
                                                                                                                                                                                                                 before such time as a new
                                                                                                                                                                                                                 EU M! version is available.
                                                                                  EU eCTD Specification Change Requests
       #            Requestor           Specification                                       Description                                                           Comments                         Status                    Action                         Group Where Action
                                         Component                                                                                                                                                                                                          is Sitting
CR-20080514-01      Anne Mieke    EU Module 1             Since this information is mandatory in the cover letter, variation and renewal        Refer to eCTD Interlinking Group for               Open                      Complete the survey for    TIGes
                     Reijnders,   Specification v1.2.1    application form and is useful for retrieving information from the eCTD               discussion and drafting of Q&A on what is                                    MS on requirements for
                  eCTDConsultancy                         lifecycle it would be beneficial to add the Marketing Authorization Numbers           expected in that field. Draft survey for MS on                               application/procedure
                                                          to the EU M1 envelope information                                                     requirements for application/procedure                                       number, and use of this
                                                                                                                                                number, and use of this element.                                             element. Once results have
                                                                                                                                                                                                                             been gathered, produce a
                                                                                                                                                                                                                             new change request as
                                                                                                                                                                                                                             appropriate requesting a
                                                                                                                                                                                                                             change to the way
                                                                                                                                                                                                                             application numbers are
                                                                                                                                                                                                                             captured in the envelope.
                                                                                                                                                                                                                             Based on the technical
                                                                                                                                                                                                                             guidance given in the new
                                                                                                                                                                                                                             eCTD specification,
                                                                                                                                                                                                                             produce associated
                                                                                                                                                                                                                             business guidance on how
                                                                                                                                                                                                                             each application number
                                                                                                                                                                                                                             element is to be used. (KM
                                                                                                                                                                                                                             to complete survey and
                                                                                                                                                                                                                             submit CR as appropriate
                                                                                                                                                                                                                             in collaboration with
                                                                                                                                                                                                                             industry)

                                                                                                                                                                                                                             Produce interim guidance
                                                                                                                                                                                                                             relating to current EU M1
                                                                                                                                                                                                                             specification and the use of
                                                                                                                                                                                                                             application numbers,
                                                                                                                                                                                                                             before such time as a new
                                                                                                                                                                                                                             EU M! version is available.

 CR-20080514-02   Kevin Wing,     EU Module 1             The EU Module 1.2.1 specification only includes instructions relating to 1.3.1        TIGes 6 March 09 : Progress revised Q&A that Open                            CR originator to draft a       TIGes
                  eCTDConsultancy Specification v1.2.1    SPC, Labelling and Package Leaflet identifiers and Language/Country                   incorporates 'refer to regional guidance' for                                proposal for the
                                                          Codes in the context of document filenames/folder paths. This information is          ICH Q&A 57 relating to the use of xml:lang                                   information, to be included
                                                          also required as XML metadata and this change request is to update the                                                                                             in the next version of the
                                                          specification to clarify this requirement.                                                                                                                         specification.
CR-20080514-03      Anne Mieke     EU Module 1            Since sequence numbers do not have to be used in sequential order it                  The Cover Letter and tracking table if             Rejected                  None
                     Reijnders,    Specification v1.2.1   would be beneficial to add the submission date back into the EU M1                    appropriate should be used to track the date -
                  eCTDConsultancy                         envelope information.                                                                 it is not useful ot have it in the envelope.
  CR-20080610     Andrew Marr, GSK EU eCTD Validation     EU validation criterion #37 defines that no file should have been scanned at                                                             Implemented in EU        Implemented in EU
                                   Criteria               a dpi of more than 300. The ETICS testing demonstrated that it does not                                                                  validation criteria v2.0 validation criteria v2.0
                                                          appear possible to assess a pdf file and determine what the scan resolution
                                                          used to produce the file actually was. It is proposed that this criterion is
                                                          deleted.
 CR-20080610-01   Andrew Marr, GSK EU eCTD Validation     EU validation criterion #45 refers to EU Q&A as its reference. This is                Check all references                              Implemented in EU          Implemented in EU
                                   Criteria               incorrect as it is ICH Q&A 36 - change reference.                                                                                       validation criteria v2.0   validation criteria v2.0
 CR-20080610-02   Andrew Marr, GSK EU eCTD Validation     There is an inconsistency between EU validation Criterion #11 and #18                 Change criterion #18 to indicate that the title   Implemented in EU          Implemented in EU
                                   Criteria               relating to the title field when the delete operation is used. #11 states „Every      should be included when delete is used, but       validation criteria v2.0   validation criteria v2.0
                                                          leaf or node extension 'title' attribute is not empty‟. #18 states „If the value of   included a statement to indicate that this is not
                                                          the operation attribute is delete,……title is not required…..Consistency               consistent with the ICH criterion #20.
                                                          should be introduced.                                                                 Create an ICH CR to indicate that ICH criterion
                                                          Additionally the wording of #11 could be improved to state “No leaf or node           #20 should refer to regional guidance.
                                                          extension 'title' attribute is empty”
                                                          Even if this is changed then there is still inconsistency.
                                                          Either – agree that the title should be included when delete is used –
                                                          change #18 but this would require a change to ICH Q&A36 #20
                                                          Or – agree that title remains optional and therefore modify #11 to provide an
                                                          exception when the delete is used.
                                                                                 EU eCTD Specification Change Requests
       #            Requestor          Specification                                      Description                                                      Comments                       Status               Action                         Group Where Action
                                        Component                                                                                                                                                                                             is Sitting
 CR-20080514-04   Kevin Wing,     EU Module 1             The concept of the Regulatory Activity was introduced within the EU 3 years      Refer to guidance on use of related sequence, Accepted - refer to   Refer to Q&A                   Interlinking
                  eCTDConsultancy Specification v1.2.1    ago and has been presented/discussed at conferences, implemented by              which has been improved and is robust with    Q&A
                                                          some vendors and is included as a term in the EMEA‟s Q&A Relating to             EU M1 v1.3.
                                                          Practical and Technical Aspects eCTD Submission (7th February 2008).             EMEA Q&A guidance should be amended to
                                                                                                                                           refer to EU guidance on use ofrelated
                                                          The “Example of the use of the Related Sequence” section on page 11 of           sequence, but to indicate that application
                                                          the EU M1 eCTD guidance describes use of the related sequence element            number is used in addition. Dependency on
                                                          to groups eCTD sequences into 3 Regulatory Activities (an MAA, a technical       CR-20080514 and the drafting of guidance for
                                                          variation and a labelling change variation).                                     use of and requirements for application
                                                                                                                                           numbers by all agencies.
                                                          In the afore-mentioned EMEA Q&A document, it is the Application Number           March-09 : Confirmed as pending, awaiting
                                                          (procedure number) that is described as the “envelope element which is           TIGes action on use of Application/Procedure
                                                          used to group together submissions relating to a particular regulatory           Numbers
                                                          activity”.

                                                          Could the TIGes provide feedback/guidance on whether the Application
                                                          Number or Related Sequence is the element used to group sequences
                                                          together within a Regulatory Activity. If the Related Sequence is not used for
                                                          grouping together Regulatory Activities, could the TIGes comment on what
                                                          value this element is adding to the EU specification?


CR-20080514-05      Anne Mieke    EU Module 1             The application number element description on page 9 of the guidance             See CR-20080514-04 -guidance to be            Open                  Complete the survey for    TIGes
                     Reijnders,   Specification v1.2.1    states that this is the “number assigned to the application by the receiving     produced.                                                           MS on requirements for
                  eCTDConsultancy                         agency”. Given the explanation provided on page 14 of the EMEA‟s recently                                                                            application/procedure
                                                          released Q&A on eCTD Implementation (7th February 2008) we presume                                                                                   number, and use of this
                                                          that for Centralised Submissions, the EMEA procedure number is meant                                                                                 element. Once results have
                                                          here (see accompanying change request).                                                                                                              been gathered, produce a
                                                                                                                                                                                                               new change request as
                                                          In DCP, MRP and especially National Procedures already several numbers                                                                               appropriate requesting a
                                                          are used to identify a submission. To avoid misunderstanding clear                                                                                   change to the way
                                                          definitions and guidance of what number to use where is needed.                                                                                      application numbers are
                                                                                                                                                                                                               captured in the envelope.
                                                          For instance in The Netherlands for a MRP submission the MRP procedure                                                                               Based on the technical
                                                          number and a case number has to be used (and of course the MA number).                                                                               guidance given in the new
                                                                                                                                                                                                               eCTD specification,
                                                          Could the TIGes provide feedback/guidance on the definition of the                                                                                   produce associated
                                                          Application Number element for MRP, DCP and National Procedures.                                                                                     business guidance on how
                                                                                                                                                                                                               each application number
                                                                                                                                                                                                               element is to be used. (KM
                                                                                                                                                                                                               to complete survey and
                                                                                                                                                                                                               submit CR as appropriate
                                                                                                                                                                                                               in collaboration with
                                                                                                                                                                                                               industry)

                                                                                                                                                                                                               Produce interim guidance
                                                                                                                                                                                                               relating to current EU M1
                                                                                                                                                                                                               specification and the use of
                                                                                                                                                                                                               application numbers,
                                                                                                                                                                                                               before such time as a new
                                                                                                                                                                                                               EU M! version is available.

  CR-20080627     NMs Nadine        EU M1 Specification   As a manufacturer for plasma products, CSL have eCTDs for products          Article 61(3) exists as a submission type in the Rejected
                  Schwarz, CSL      v1.3                  which are registered under the Central Procedure and the Mutual             EU M1 specification v1.3
                  Behring AG                              Recognition Procedure. For either procedure, the CMD(h) STANDARD
                                                          OPERATING PROCEDURE PROCEDURE FOR ARTICLE 61(3) CHANGES
                                                          TO PATIENT INFORMATION (Rev. 1, July 2007) is applicable. By this
                                                          procedure, administrative changes to the product information, such as
                                                          corrections of typographical errors, may be notified to EMEA or RMS instead
                                                          of submitting a variation.
                                                          If this is done for an existing eCTD, there is no adequate submission type
                                                          defined in the Module 1 Specification to describe this submission.
                                                                                EU eCTD Specification Change Requests
      #             Requestor         Specification                                      Description                                                      Comments                        Status                 Action                      Group Where Action
                                       Component                                                                                                                                                                                             is Sitting
 CR-20080703     Andrew Marr       EU M1 Specification   The list of submission types included in the eCTD Module 1specification As part of the creation of EU Module 1, v1.3             Accepted - refer to    Produce Q&A and update      Interlinking
                 (EFPIA)           v1.3                  v1.3 does not include Repeat Use Procedure. What submission type should and in conjunction with the development of the           Q&A and include in     Best Practice Guidance
                                                         be used for this submission?                                            eCTD in MRP/DCP Best Practice document                   updated Best
                                                                                                                                 consideration was given to the creation of               Practice Guidance
                                                                                                                                 „Repeat Use Procedure‟ as a specific
                                                                                                                                 submission type. After deliberation, this was
                                                                                                                                 not accepted. However, the Best Practice
                                                                                                                                 Guide did not include any recommendation for
                                                                                                                                 which submission type should be used. In
                                                                                                                                 discussion at the eCTD Interlinking Group it
                                                                                                                                 was proposed that „Initial MAA‟ should be used
                                                                                                                                 and that a Q&A should be prepared to this
                                                                                                                                 effect.
                                                                                                                                 The submission type that should be used is
                                                                                                                                 „initial-maa‟ since this is the initiation for the
                                                                                                                                 new Concerned Member States. The
                                                                                                                                 submission description should be „Repeat Use
                                                                                                                                 Procedure‟.
                                                                                                                                 March-09 : Interlinking agreed that as an
                                                                                                                                 interim, a Q&A would be produced and in the
CR-20080703-01   Andrew Marr       EU M1 Specification   The list of submission types included in the eCTD Module 1specification As part the development of the eCTD in                   Accepted - refer to    Produce Q&A                 Interlinking
                 (EFPIA)           v1.3                  v1.3 does not include a specific submission type for a change of the    MRP/DCP Best Practice document it was                    Q&A
                                                         Reference Member State in MRP. What submission type should be used for agreed that „Change of RMS‟ would utilise an
                                                         this submission?                                                        existing submission type and that a Q&A
                                                                                                                                 should be prepared to this effect.
                                                                                                                                 The submission type that should be used is
                                                                                                                                 „supplemental-information‟ and the submission
                                                                                                                                 description should be „Change of Reference
                                                                                                                                 Member State‟
                                                                                                                                 March-09 : CMD(h) reviewing guidance on
                                                                                                                                 change of RMS. Q&A to be produced to
                                                                                                                                 explain how change should relate to eCTD.

 CR-20080806     Remco Munnick,    EU M1 Specification   In the text of page 16, under nr 4 it mentions: 'Note that the tracking table    Include the common folder in the examples for Accepted                 Implement in next version   Interlinking
                 Sandoz            v1.3                  required with MPR/DCP submissions should be located within a 'common'            MRP on page 37                                                         of EU M1 specification.
                                                         directory, with the filename 'tracking.pdf' or 'tracking.xml‟.                   Include the tracking table in the example for                          Also update the example
                                                         However when you look to the examples for MRP and DCP, the tracking              MRP and DCP on page 45.                                                XML on p.45
                                                         table is not included in the folder m1/eu/10-cover/common.                       March-09 : Confirmed by Interlinking
                                                         Also in the screenshot on page 37, there should be a common folder under
                                                         m1/eu/10-cover, which is missing.

 CR-20080903     Alastair Nixon,   EU M1 Specification   Copy requirements for eCTDs should be different from other electronic            Electronic copy requirements for Type IA and    Implemented in new     Dossier requirements
                 GSK               v1.3                  dossiers – all CHMP members should get an electronic copy of everything,         IB variations are split by NeeS and eCTD. For   dossier requirements   updated April 2009
                                                         including Type IA/IB variations – otherwise future lifecycle operators will be   NeeS, they stay as they are. For eCTD, the
                                                         invalid.                                                                         requirements for Type IA and IB variations
                                                         The current copy requirements do not differentiate between eCTD and              mirror those for Type II – i.e. “Other CHMP
                                                         NeeS. For Type IA and IB variations, only the Rapporteur requires 2              members: 1 electronic copy”.
                                                         electronic copies,
                                                         other CHMP members get nothing. However, a Type IA variation can
                                                         amend a significant piece of content in the dossier. For example, a
                                                         Category 12a variation to tighten a specification will modify S4.1. A future
                                                         Type II variation could result in a replacement active specification being
                                                         submitted, but the if the original change had not been uploaded by an
                                                         agency, the modified file in the second change will be invalid. In addition,
                                                         any countries not uploading all sequences will get an incorrect „current view‟
                                                         for the application.
                                                                             EU eCTD Specification Change Requests
      #             Requestor         Specification                                   Description                                                       Comments                         Status              Action                       Group Where Action
                                       Component                                                                                                                                                                                          is Sitting
CR-20080903-01   Alastair Nixon,   MRP/DCP Best        The requirement for a cover letter in local language means that applicants      For submissions not requiring an application    Implemented           March 2009 CMD(h) press
                 GSK               Practice Guidance   preferring to centralise electronic dossier production, or following the        form, a single „common‟ English language                              release included statement
                                                       preferred „Comprehensive model‟ for eCTD in MRP/DCP must get a cover            cover letter is acceptable in all MS.
                                                       letter translated into all European languages before building the dossier.      Identified as a hurdle for eCTD
                                                       For submissions requiring an application form, this is unavoidable, since the   implementation. Cover letter is not covered by
                                                       form contains details of the MAH, and local contacts etc. However, for follow   legislation, but nevertheless some MS have
                                                       up measures, or simple administrative submissions, the requirement to get a     requirements for local laguage versions. HMA
                                                       cover letter translated up to 23 times is onerous and does not add value to     to try to persuade individual agencies to relax
                                                       the dossier (NB the rest of the content is likely to be in English). Could a    requirements for a cover letter in the local
                                                       „common‟ English language cover letter be used for such submissions?            language. This should not be a requirement -
                                                                                                                                       one cover letter in EN should be accepted by
                                                                                                                                       all MS. ACTION: Applicants to inform
                                                                                                                                       Interlinknig group of any MS asking for local
                                                                                                                                       language cover letters, and the group will try
                                                                                                                                       to dissuade these MS. Also indicate if these
                                                                                                                                       MS have local letter templates or are asking
                                                                                                                                       for the general cover letter to be translated.
                                                                                                                                       Also include information as to whether the MS
                                                                                                                                       ask for this cover letter to be in the eCTD.
                                                                                                                                       March-09 : Updated national requirements
                                                                                                                                       table should address but press release will
                                                                                                                                       indicate that there should be no additional
                                                                                                                                       national requirements. Consideration to be
                                                                                                                                       given to identification of point of contact is
                                                                                                                                       NCAs request/require additional national
                                                                                                                                       specifics.
 CR-20080909     Leigh Sandwell,   eCTD Guidance       Current guidance requires that statements justifying absence of data in the     Recommend that empty Module 1 Sections do Implemented in              Agreed wording include in
                 Pfizer                                eCTD should be provided in the QOS, non-clinical and clinical overviews, as     not require a justification statement to be     Harmonised Guidance   Harmonised eCTD
                                                       applicable, and that no placeholder documents are required in the eCTD          included in each section and the Q&A                                  Guidance v1.0
                                                       structure. The guidance should be updated to clarify how to deal with empty     document is updated to reflect Module 1.
                                                       sections of Module 1 and any potential justification that may be required.
                                                                                                                                       Approach to M1 is different than for other
                                                                                                                                       modules, as M1 should always be populated
                                                                                                                                       (even with 'not applicable' statements) as a
                                                                                                                                       legal requirement. Another proposal is that
                                                                                                                                       only justifications should be required - simple
                                                                                                                                       statements of not applicable should be
                                                                                                                                       included in the cover letter. Revisit this
                                                                                                                                       discussion as currently no agreement.
                                                                                                                                       March-09 : Principle that empty sections
                                                                                                                                       where no justification for absence is required
                                                                                                                                       should be listed in the Cover Letter. Proposal
                                                                                                                                       to provide statement in Harmonised eCTD
                                                                                                                                       Guidance. Wording to be confirmed by
                                                                                                                                       Interlinking Group.
                                                                                                                                       April -09 : decision modified and agreed
                                                                                                                                       statement included in Harmonised guidance -
                                                                                                                                       Section 3.2.1
                                                                               EU eCTD Specification Change Requests
      #             Requestor          Specification                                   Description                                                     Comments                        Status                 Action                      Group Where Action
                                        Component                                                                                                                                                                                         is Sitting
CR-20080909-01   Dietmar Boecker,   eCTD Guidance        Guidelines on the submission of the EU-RMP require a stand-alone format                                                       Accepted               Refer to EMEA eCTD          EMEA
                 Bayer Schering                          of the document including all annexes to be located in eCTD Module 1.8.2.                                                                            Business Team for
                                                         This is in contradiction to the ICH eCTD requirements, that mandates a                                                                               discussion and
                                                         different location for most of the annexes.                                                                                                          confirmation, and amend
                                                         In section 4.4 of the EU-RMP guideline EMEA/CHMP/96268/2005 it is                                                                                    all guidance documents as
                                                         outlined that the EU-RMP "should be provided (...) in a stand-alone format                                                                           appropriate.
                                                         allowing circulation to, and evaluation by pharmacovigilance and risk
                                                         management experts". The same requirement is defined by the Pre-
                                                         Submission guide in response to question 36. The template for the EU-RMP
                                                         (EMEA/192632/2006) lists 8 Annexes, which should be provided in eCTD
                                                         Module 1.8.2 together with the main body of the RMP. However, some of the
                                                         annexes like the current SPC have already well defined locations in other
                                                         Modules of the eCTD.
                                                         For the location of the EU-RMP annexes it is proposed to update the
                                                         guidelines mentioned above, so that applicants should cross refer from the
                                                         EU-RMP to other locations of the eCTD where appropriate. With the
                                                         exception of the annex 1, all annexes would be affected:

 CR-20081023     Remco Munnik,      EU Module 1          Discrepancy in guidance on where to store additional documentation for       The CTD Q&A 4c is correct and should be           Accepted - refer to   Review content of Renewal Interlinking
                 Sandoz (EGA)       Specification v1.3   variations that do not have a place in CTD structure. No guidance for        observed - Where documents cannot be              Q&A                   Guidance
                                                         renewals is available.                                                       assigned to specific CTD-defined locations
                                                                                                                                      then they should be included in 1.2 Application
                                                                                                                                      Form. These might include declarations,
                                                                                                                                      certificates, justifications etc. Where possible,
                                                                                                                                      they should be organised according to the
                                                                                                                                      Annexes for the Application Form for new
                                                                                                                                      products (Annexes 1 to 22). Where
                                                                                                                                      documents cannot be assigned to one of the
                                                                                                                                      annexes then it is appropriate to place them
                                                                                                                                      after the annexes. The „Additional Data‟
                                                                                                                                      section of Module 1 should not be used except
                                                                                                                                      for country-specific information.
                                                                                                                                      The EU M1 specification should therefore be
                                                                                                                                      amended in the next version to reflect this,
                                                                                                                                      and a Q&A is required to confirm this, and also
                                                                                                                                      to confirm that the same approach should be
                                                                                                                                      taken for renewals.
                                                                                                                                      March-09 : Interlinking to confirm that referral
                                                                                                                                      to Renewal Guidance is sufficient

 CR-20081008     Andrew Marr,       eCTD specification   The guidance just issued by QRD regarding production by the applicant of         Dec 08: EMEA meeting held to discuss issue - Accepted               File naming convention      EMEA
                 GSK (EFPIA)        v3.2                 the PDF for final labelling is incompatible with the eCTD and will lead to       conclusion that requirements for EMEA PDFs                          agreed. Publication in User
                                                         duplication of effort.                                                           arise from the EMEA EPAR publication                                guide on how to generate
                                                         In the longer term EMEA must align their requirements and if there is            process, and eCTD filenaming requirements                           PDF versions of Product
                                                         business logic for the filename as per the EPAR proposed name then an EU         have a different purpose and support a                              Information' and 'Questions
                                                         specification change may be justified with the inclusion an appropriate          different proess (review) and therefore                             and answers relating to
                                                         filename that meets ICH general filename requirements.                           requirements cannot be aligned until Q3 2009                        practical and technical
                                                                                                                                          when the EMEA publication process is re-                            aspects of the
                                                         In the short-term there is an urgent need for clarification as to how an         designed. This conclusion was not redily                            implementation' to be
                                                         applicant can submit product information inside and outside the eCTD, for all accepted by industry - either alignment must                           updated
                                                         submission types without duplication of effort or risk of failure to validate or be sought, or at least clear guidance should
                                                         accept                                                                           be provided as to how to manage in the
                                                                                                                                          meantime, and a clear plan for resolution
                                                                                                                                          should be presented by EMEA
                                                                                                                                          March 2009 : EMEA updated PDF naming
                                                                                                                                          convention within 'User guide on how to
                                                                                                                                          generate PDF versions of Product Information'
                                                                                                                                          to be consistent with eCTD. Practical Q&A
                                                                                                                                          needs to be updated to also reflect this
                                                                                                                                          change.
                                                                                EU eCTD Specification Change Requests
    #            Requestor           Specification                                       Description                                                        Comments                       Status                  Action                     Group Where Action
                                      Component                                                                                                                                                                                               is Sitting
CR-20081210   Gerhardt          EU Validation Criteria   So far, the EU Validation Criteria do not verify the correctness of the overall   Introduce to the EU Validation Criteria an     Implemented in v2.1      Validation criteria v2.1
              Neurauter, Extedo                          checksum in the provided index-md5.txt. Guidance is given by the EMEA to          additional issue: “The checksum of the         of validation criteria   published
                                                         provide this checksum in the cover letter, however, the possibility to verify     index.xml should be calculated by a validation
                                                         the MD5 with the EURSvalidator is not given.                                      tool and compared with the checksum
                                                         Authorities not using the EURSvalidator perform checks with tools verifying       provided in the index-md5.txt.” In case of
                                                         the overall checksum. We received responses from clients that submissions         invalidity the recommended severity should be
                                                         are rejected due to invalid values in the index-md5.txt. However this issue is    A.
                                                         not part of the EU Validation Crieria.                                            TIGes 6 March 09 : Agreed to progress as an
                                                         In case of MRP/DCP we encounter troubles that submissions are accepted            urgent change and actioned to the EURS
                                                         only in regions the EURSvalidator is used.                                        group

CR-20090126                      NtA Volume 2B           The ICH M2 eCTD specification and Notice to Applicants Volume 2B provide          TIGes 6 March 09 : Principle supported. Action Answered in Q&A          Answered as Question #22
                                 Section 2.7.6           different information concerning how to deal with the Synopses of Individual      to Interlinking Group to progress. Suggested
                                                         Studies in Section 2.7.6. The guidance should be harmonised to provide a          that option of either hyperlinking to or inclusion
                                                         similar message in both the CTD and eCTD and avoid confusion.                     of synopses.
                                                         The NtA guidance states:                                                          Recommend that the NtA guidance is updated
                                                         2.7.6 Synopses of Individual Studies                                              to reflect the Section 2.7.6 guidance in the
                                                         The ICH E3 guideline (Structure and Content of Clinical Study Reports)            ICH M2 eCTD or clearly reference this
                                                         suggests inclusion of a study synopsis with each clinical study report, and       difference between the paper and electronic
                                                         provides one example of a format for such synopses.                               outputs.
                                                         This section should include the table entitled Listing of Clinical Studies,       March-09 : Interlinking agreed that
                                                         described in guidance for Module 5, followed by all individual study              hyperlinking should be an option for
                                                         synopses organised in the same sequence as the study reports in Module 5.         applicants. Q&A to be produced.
                                                         It is expected that one synopsis will be prepared per study for use in all        April-09 : Interlinking group endorsed a Q&A
                                                         regions, and that the same synopsis will be included in this section and as       for publication
                                                         part of the clinical study report in Module 5. The length of a synopsis will
                                                         usually be up to 3 pages, but a synopsis for a more complex and important
                                                         study may be longer, e.g. 10 pages. Within the individual synopsis, tables
                                                         and figures should be used as
                                                         appropriate to aid clarity.
                                                         But the ICH M2 eCTD guidance states:
                                                         These synopses should already be located in the Clinical Study Reports in
                                                         Module 5 and should not, therefore, be repeated in
                                                         Module 2. It is considered sufficient to provide hyperlinks from the listing
                                                         of the studies, located here, to the locations of the synopses in Module 5.

								
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