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					EU Region Question and Answer and Specification Change Request Document

                                           Version 1.14

                                         November 2008

                                    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
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.
#                              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 product With respect to product information (PI) documents, the currently acceptable file    Mar-2007
  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 or
    This question was generated by EU Change Request A004              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 added
  be used respectively?                                                 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 Follow-
  required as CTD/e-CTD submissions in the EU.                          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 documents   Questions, what to include in Module 1 and what to include in Modules 2-5. The
  should be attached to the Cover Letter (1.0). However, no              EU Module 1 specification Version 1.2.1 now includes the section for Responses
  recommendation is given with regard to the organisation of the table   to Questions. The CTD guidance and eCTD specification together should give
  of contents, nor to the names and organisation of the files etc. Do    adequate direction for applicants to construct a Responses to Questions dossier
  these recommendations exist?                                           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 ICH
  the structure if it has multiple substances?                           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 official
   The question was generated by ICH change request 00710 and the 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 Related A 'regulatory activity' is a logical unit of submission activity (eg, a Type II       Feb-2008
   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 eCTD
    This question was generated from EU Change Request QA-               sequence should be provided (a lifecycle sequence) correcting these errors, with
    20061120-01                                                          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 needed   Mar-2008
   component of filenames should be a “meaningful concatenation of it is suggested that the word 'point' is used in the filename eg. 1point5mg
   words without separation and should be kept as brief and
   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-20070627- structure, as these would create a document lifecycle for non-existent
   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 nor     Mar-2008
   backbone during the life an application, for example, if the         is it necessary to attempt workarounds such as deleting existing documents and
   manufacturers name changes, the proposed name of the dosage          resubmitting with new attributes. The recommendation is to retain the obsolete
   form is not accepted or an excipient is granted a pharmacoepial      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-20071002-        Decentralised Procedures and is therefore not applicable for the Centralised
   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 to
   This question was generated by EU Change Requests CR-                  the content located in module 3 e.g. Flow Chart of the Manufacturing Sites, and
   20070906-01 & CR-20070927-01                                           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 The application number element description on page 9 of the
   guidance states that this is the “number assigned to the application
   by the receiving agency”. Given the explanation provided on page
   14 of the EMEA‟s recently released Q&A on eCTD Implementation
   (7th February 2008) we presume that for Centralised Submissions,
   the EMEA procedure number is meant here (see accompanying
   change request).

    In DCP, MRP and especially National Procedures already several
    numbers are used to identify a submission. To avoid
    misunderstanding clear definitions and guidance of what number to
    use where is needed.

    For instance in The Netherlands for a MRP submission the MRP
    procedure number and a case number has to be used (and of
    course the MA number).

    Could the TIGes provide feedback/guidance on the definition of the
    Application Number element for MRP, DCP and National
    Procedures.
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.
                       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
                                                             EU eCTD Specification Change Requests
 #     Requestor      Specification                                  Description                                                     Comments                         Status                Action
                      Component
A001               eCTD EU Module 1   What is the EU's position on the use of XML for the content of the submission Change request added retrospectively to allow     Implemented in EU M1 Implement in v1.3:
                   Specification      instead of PDF and/or RTF?                                                    tracking of the Q&A process                       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 M1 Implement in v1.3:
                   Specification                                                                                    tracking of the Q&A process                       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 a Change request added retrospectively to allow         Answered in Q&A       Answered as Question #9
                                      separate subfolder. How should a product be added to the structure if it has tracking of the Q&A process
                                      multiple substances?
                                                                    EU eCTD Specification Change Requests
 #       Requestor           Specification                                  Description                                                        Comments                         Status                Action
                             Component
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 M1   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        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 not    appropriate use of node extensions in                                   section with agreed text
                                             supported in any part of the submission and this therefore invalidates the ICH   compliance with the eCTD specification (i.e.
                                             spec. Experience on production of submissions for Europe demonstrates that       their use is discouraged unless there is no
                                             node extensions are required to deliver a navigable structure for Modules 4      other feasible means to submit the information).
                                             and 5. At present this means that eCTDs are not re-usable across regions
                                             and thus will create significant amounts of rework for industry. FDA should      May 2005: Referred to EU and MHLW regional
                                             accept node extensions in Modules 2-5.                                           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 M1 Implement in v1.3:
       generated by ICH   Specification                                                                                       regional guidance                                 v1.3                 Answered as Question 11.
       change request                                                                                                                                                                                Put a comment in appendix
       00710                                                                                                                  June 2005: Applicant stylesheets are accepted                          2,row 72.
                                                                                                                              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 different Answered in Q&A          Answered as Question #13
                          Specification      commonly misinterpreted that would prevent my eCTD message from being            interpretations of the eCTD Specification that                          and covered by EU
                                             viewed by another applicant/regulator?                                           have prevented timely exchange of eCTD                                  Validation criteria.
                                                                                                                              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
                               Component
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 been         It may be possible to have an additional         Implemented in EU M1 Opened 19-09-2004
       (EFPIA)              Specification v1.0   created it is not possible to know what each sequence is about with physically    attribute assigned to the submission type        v1.1                 Agreed 24-09-04
                                                 opening the sequence documents and reading the Cover Letter. Industry is          „submission description‟. This could be either
                                                 already considering requesting the vendors to provide some additional             optional or mandatory dependent upon                                 Dec 05: Implemented in
                                                 description to assist in creation of the applications and we understand that at   submission type.                                                     eCTD Spec v1.1 - new
                                                 least the EMEA is adding a description to this Docubridge records. It would                                                                            element 'submission-
                                                 be logical to standardise on an additional attribute that the applicant can                                                                            description' added to
                                                 complete for there own records and that the agencies can make use of in their                                                                          envelope.
                                                 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
       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 agencies.                                                                               R. de Boer to split the CR
                                                 This change request is made to enable the AF to be used during MRP                                                                                     into those points that are
                                                 submissions. Some of the requests made below are suitable for none MRP                                                                                 nice to have and those
                                                 subm as well.                                                                                                                                          which are essential
                                                 Generic apps - It should be possible to include reference medicinal products                                                                           requirements
                                                 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 that                                                                       and in CTD Q&A.
                                                 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
                           Component
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 to
                                             procedure - Mutual recognition procedure- Independent National procedures- Referred to Notice to Applicants Group                                            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 in Implemented in EU M1   Dec 05: Implemented in
                        Specification          submitted using XML, so the PIM DES does the same for product information.        accordance with the PIM DES' should be            v1.2.1                 eCTD Spec v1.1 - accepted
                                               The current EU Module 1 specification permits PDF and RTF as formats for          detailed, as this standard includes more than                            file formats amended.
                                               product information, but not XML. For administrative information, however,        XML (additional documents that can be                                    Oct 06: Updated in eCTD
                                               XML is permitted. Suggestion : Include XML as an accepted format for the          attached with the XML)                                                   Spec v1.2.1 - accepted file
                                               “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 folder   Retain separate util folder for components that Implemented in EU M1 Oct 06:
       Kumar)           Specification          that includes STYLE and DTD folders. The screen shots are good and                can be submitted outside eCTD e.g. e-AF and v1.2.1                   Implemented in eCTD Spec
                                               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 we    util folder to obviate need for regional util folder.
                                               have a DTD folder.This structure is clear and consistent across all regions as    More testing required of PIM container
                                               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 of eCTD EU Module 1      EU Module 1 Specification:                                                                                                       Implemented in EU M1 Dec 05: Implemented in
       Medicines (José   Specification         Element : m1-6-1-non-gmo                                                                                                         v1.1                 eCTD Spec v1.1, cell 43
       Manuel Vidal                            Directory : m1/eu/16-environrisk/161-nongmo                                                                                                           p.21
       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
                            Component
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 M1 Dec 05: Implemented in
       Marr)             Specification v1.0, EAF approval in Europe, that of the Decentralised Procedure. In the current eCTD                                                      v1.1                 eCTD Spec v1.1 new
                         v1.0                    envelope a picklist provides for the option of Centralised, Mutual Recognition                                                                         attribute in envelope.
                                                 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 M1 Dec 05: Implemented in
                       Specification             per the road map (DES 2.1), for December 2005.                                    will need to be created in EU M1 for            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 will Deferred             Referred to ICH for next
                         v3.2                    system interoperability (EURS/PIM RS) for regulators for them to make PIM         consider for the scope of the next major release                     major version of the eCTD.
                                                 submissions to applicants either with or without eCTD.                            (ICH Change Request #1110)
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 the Implemented in EU M1 Dec 05: Implemented in
                          Specification          and „national‟ as folders between the root folder and the sequence number.        „procedure‟ folders deleted. This should       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
                            Component
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 implementation Answered in Q&A      Answered as Question #14
                          Specification      sequences indicates that we should refer to regional guidance with respect to      of the eCTD, the four Operation Attributes
                                             allowance of cross-referral. This guidance needs to be established.                (new, append, replace and delete) will remain                        Referred to ICH for next
                                             ICH Question: The eCTD specification supports the ability to refer to a            and not be added to. With the existing                               major version of the eCTD.
                                             previously submitted file, for example, by including in sequence 0005 a leaf       specification it is technically possible to
                                             with Operation Attribute of 'new' that refers to a file submitted in 0000. Is it   determine that a file is not in the current
                                             possible to indicate to the reviewer that they have already received and           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 1.          Recommended solution                             Implemented in EU M1 Oct 06: Implemented in
                        Specification        This CR requested the following actions:                                           - Add TGZ as allowed file format (this format is 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 the        - Add name specification “131-pim-xxxx-
                                             image formats (JPEG, GIF, PNG, TIF, SVG, MathML)                                   ar.zip/tgz ” for the PIM file
                                             Today, PIM systems are under elaboration and practical experience provided         - Keep Element “m1-3-1-pim”
                                             some feedback about the way PIM has been integrated into the EU Module 1.          - Remove description the use of EU M1 “util”
                                             Following the feedback received, we believe that there is a simpler way to         folder for PIM
                                             include PIM in EU Module1.                                                         - Remove definition of folder “131-pim-xxxx-ar ”
                                             It is more appropriate to include PIM into the EU Module 1 as a single archive
                                             file than directly refer to the XML file. Therefore, it is proposed to:            Refer to PIM DES specifications for
                                             - Add ZIP format and TGZ format as valid file formats                              compression protocols
                                             - 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
                                     Component
   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 as                                                Implemented in EU M1 Oct 06: Implemented in
                                  Specification            defined by ICH in the context of eCTD. The leaf entity is defined by:                                                          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 M1 Implemented in EU Module
              Liquent, Thomson    Specification            Module 1 eCTD version 1.1 specification indicates that the corresponding          Check guidance is clear                      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 Module          Addressed by EU M1 v1.3 specification and    Closed                 None
              Kendle              Specification and type   1 specifications issued in January 2006 become mandatory for use in all           transition plan
                                  definition               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 the                                                 Implemented in EU M1 Implement in v1.3:
                                                           eu-regional.xml in the index.xml?                                                                                              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 be
                                                           documents obsolete. It is also not new, because the eu-regional.xml has been                                                                        'new'. Investigate other
                                                           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 for             EU M1 is 1st priority – Lang/country codes for Implemented in EU M1 Implemented in EU Module
              Roche               Specification, v1.2 the planned accession of Romania and Bulgaria. Version 1.2 of the DTD                  RO BU in DTD, specifications and style-        v1.2.1               1 eCTD v1.2.1
                                                      included several changes, including the removal of these country and                   sheet. Assessment of required changes to
                                                      language codes. Given the planned accession date of 1st Jan 2007, we                   align 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
                                         Component
 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 included Closed                  None
                 Liquent              Specification, v1.2 managed by an eCTD how should the operations attributes be used?                       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
                                  Specification, v1.2 eCTD                                                                                       documents should be handled in the same way eCTD Interlinking         detailing the guidance to
                                                                                                                                                 that the SPC is currently handled in eCTD -     Group                 submit only the final agreed
                                                               Currently with a paper submission there is the possibility of submitting a        only the final agreed versions of the documents                       version of the M3
                                                               response to a question which may contain a proposal (e.g. a change to the         should be submitted at (or just before) the end                       documents in the eCTD.
                                                               specification) and when that is found to be acceptable by the regulators the      of the procedure. The interim versions should                         (This will set a precedent for
                                                               revised Module 3 content can be submitted. With an eCTD is it always              not be exchanged in the eCTD - they should be                         an eCTD Q&A and any
                                                               expected that the Module 3 section is updated at the time of submitting the       exchanged as communications outside the                               appropriate guidance
                                                               response or can this also be delayed until it is known that the response is       eCTD.                                                                 change).
                                                               acceptable?
 20060703-01     Geoff Williams,      EU Module 1 DTD and                                                                                                                                        Implemented in EU M1 Implemented in EU Module
                 Roche                Specification, v1.2 The European Commission website URL is incorrect                                                                                       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 M1 Implemented in EU Module
                 Roche                Specification, v1.2 The example filenames given for two documents in the specification are                                                                 v1.2.1               1 eCTD v1.2.1
                                                          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
                 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 Bruggen, 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         Deferred              Discussed at ICH M2, see
                 eCTDConsultancy Appendix 6                    submitted.                                                                        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.
                                                                                    EU eCTD Specification Change Requests
      #             Requestor           Specification                                        Description                                                        Comments                        Status                 Action
                                        Component
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 group,
                                                            rapporteur and co-rapporteur have at this stage already received an initial         they responded "It is required to submit the
                                                            copy of the eCTD.                                                                   application to Rap / Co-Rap at the same time
                                                            (i) How is the applicant advised to handle validation changes in the eCTD?          as to the EMEA. It is therefore not possible to
                                                            Should another eCTD sequence be created, incorporating the suggested                submit to Rap / Co-Rap only after validation of
                                                            changes, or should the original sequence be corrected? NB If an additional          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 the Duplicated                          None
                 Datafarm           specification v1.2.1    inconsistent with the accompanying statement that „common‟ is the directory 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 M1 Implement in v1.3:
                 J&JPRD             specification v1.2.1,   variable component of filenames should be a “meaningful concatenation of                                                            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 these                                                                          specification 'file naming
                                                            variable components. The change request applied for is to allow the use of                                                                               convention'
                                                            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 M1 Implement in v1.3:
                 America           specification v1.2.1,    regarding the Specifications.                                                                                                       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 M1 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 reflect v1.3                 Change the 3 examples in
                                   examples                 examples, this folder contains the EU Module 1 DTD files. This is incorrect         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 to instatement of max. 50 character field length.
                                                            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
                                       Component
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, it                                                                          ICH tracking sheet for
                                                             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 M1 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.                         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 a     Write a Q&A to clarify until new version is                          text which illustrates this on
                                                             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                                                                                                                                        Rejected               Discussed at ICH M2, see
                 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?
                                                             A. The regulatory authority should be consulted for a solution until the 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, item 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                 Deferred               Discussed at ICH M2, see
                 Roche              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 xlink:href discussion and position taken at an EU level.
                                                         should exist. At the time this was written, we probably meant “exist 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
                 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
                                         Component
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
                 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.

                                                             The change request says that the element for Module 3.2.A.3 (Novel
                                                             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
                 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.
CR-20070426-01   Joe Cipollina, BMS ich-stf-stylesheet-2-    The ICH STF Stylesheet currently posted gives inconsistent display results in     This CR/Q&A was submitted to the ICH M2         Deferred              Discussed at ICH M2, see
                                    2.xsl                    Internet Explorer. It seems to work in some cases but not in others. STF files    group for consideration. It has been added                            ICH tracking sheet for
                                                             which were viewable with the older version of the stylesheet are no longer        here for completeness and to record any                               details of outcome.
                                                             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 the This CR/Q&A was submitted to the ICH M2         Deferred              Discussed at ICH M2, see
                                                             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 is Nov-07 Q&A wording proposed                     Implemented in EU M1 Implement in v1.3:
                 GSK                                         not provided, and there is no need for the applicant to provide „not applicable‟                                                  v1.3                 Answered asQ&A #18.
                                                             pages. However, we have experienced occasions where we receive                                                                                         Change text on p.6 to
                                                             questions after EMEA content validation with respect to sections that are                                                                              include text from Q&A 18.
                                                             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 M1 Implement in v1.3:
                 GSK                  specification v1.2.1   response to questions                                                             specification                                   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>? The         use of related-sequence attribute
                                                             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 to Implemented in EU M1 Implement in v1.3 if values
                 Ethypharm            specification v1.2.1   standardised the value of this element.                                           define list                                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 / dextroproxifen), Sep-07 Requested to be withdrawn and                Withdrawn             None
                 Ethypharm                                   what is the best practice : duplicate <atc> and <inn> element ?               resubmitted as a CR (subsequently submitted
                                                                                                                                           as CR-20070718-01)
                                                                                     EU eCTD Specification Change Requests
      #             Requestor            Specification                                        Description                                                        Comments                          Status                Action
                                         Component
QA-20070628-04   Thierry Le Ridant,   eCTD EU Module 1        DCP or MRP are followed by a national phase (PIL etc.). What should be the        Response provided in Best Practice guide for       Closed                None
                 Ethypharm            specification v1.2.1    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 stylesheet Data from the envelope is displayed in blue but they are not hyperlinks. The       Sep-07 Analysis undertaken of all EU               Implemented in EU M1 Implement in v1.3:
                 Ethypharm                                   use of blue text should be limited to hyperlinks                                   stylesheets shows inconsistency. Change            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
                 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-New Deferred                     Refer to eAF project -
                 eCTDConsultancy                              filepaths for the xlink:href attribute value                                      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 is   Nov-07 Was referred to eCTD Interlinking           Accepted - refer to   Propose to eCTD
               Ethypharm              specification v1.2.1    no link between the <inn> element and the <atc> element. We suggest to            Group "No changes required – Because there         eCTD Interlinking     Interlinking/TIGes that atc is
                                                              regroup them into an <active> element which will permit to identify the link      is no one to one relationship between              Group                 removed altogether from the
                                                              between atc and inn.                                                              substance and atc codes. The codes relate to                             envelope.
                                                                                                                                                the indication of the product."                                          Request information from
                                                                                                                                                Subsequent research shows this may not be                                EMEA and MS on use of atc
                                                                                                                                                correct.                                                                 code. Needs further
                                                                                                                                                June 2008: eCTD Interlinking: ATC code left in                           clarification.
                                                                                                                                                EU M1 v1.3                                                               Await development of the
                                                                                                                                                Dec 08: Interlinking Group - there is definitely                         eAF where the ATC will be
                                                                                                                                                no link between the substance and the                                    processed.
                                                                                                                                                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).
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 period
                                                              Further detail included in original question.
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 -
                 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
                                                                                        EU eCTD Specification Change Requests
      #             Requestor           Specification                                            Description                                                          Comments                       Status                 Action
                                        Component
QA-20070906-01 Hans van Bruggen, eCTD EU Module 1               Could the TIGes clarify what <Submission> “type” attribute value should be           Nov-07 Review required across other             Implemented in EU M1 Implement in v1.3:
               eCTDConsultancy specification v1.2.1             selected for the following types of submission:                                      specifications. See also CR-20070926-01         v1.3                 Propose revised list. See
               B.V.                                             1. Annual Reassessment                                                                                                                                    CR-20070926-0 - ensure
                                                                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 M1 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.         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
                 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 M1 Implement in v1.3:
                 Montes, EMEA        specification v1.2.1                                                                                            specifications. See also QA-20070906-01         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 M1 Implement in v1.3:
                 AstraZeneca         specification v1.2.1 and   specification to be submitted. The basis for eCTD is to submit documents             defines how to reference content from more      v1.3                 Include a short additional
                                     Guidance on Type 1A        only once, but to be able to fulfil the European variation guidelines all required   than one leaf location. Some clarity might be                        section on p.6 under
                                     and 1B variations          documents would need to be submitted. This change request gives a                    added to specification.                                              'General Architecture'.
                                                                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 Winkel, Notice to Applicants vol The ASMF guidelines state that the manufacturer and the applicant should                Nov-07 This issue is referrd to the NtA Q&A on Deferred                Refer to NTA Q&A
                 N.V. Organon       2B                       both submit an identical Applicant‟s Part (AP) of the EDMF.                             handling of ASMF
                                                             Guidelines for eCTD files indicate that the AP should be included in Section
                                                             3.2.S of the eCTD.
                                                             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 discussion Deferred                Referred to Harmonisation
                 i3Logic                                        lifecycle of an application?                                                         and position                                                           Tasforce

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 section Implemented in EU M1   Answered as Question 20
                 Montes, EMEA        specification v1.2.1       centralised procedures?                                                              can be used for CP in a transition period for   v1.3                   Refer to CTD Guidance #4
                                                                                                                                                     submitting documents as part of a new M1                               on use of the additional data
                                                                                                                                                     structure before the latest DTD version is                             section (i.e. it should not be
                                                                                                                                                     implemented (e.g. paediatrics data).                                   used for CP) - amend
                                                                                                                                                                                                                            therefore line 68 of the table
                                                                                                                                                                                                                            in appendix 2
                                                                                   EU eCTD Specification Change Requests
      #             Requestor         Specification                                         Description                                                       Comments                        Status                Action
                                      Component
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 M1   Accepted for next minor
                 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 in v1.3                   update of EU Module 1
                                                          annex to the form (p14). It is proposed that all supporting data is provided in     Variations. Accepted to update EU M1 eCTD                             eCTD
                                                          the same location, as an annex to the form. In addition, it is proposed that a      specification in line with CTD Q&A response.                          Amend Appendix 2 row 67,
                                                          table of suggested names is added to the specification, such that these                                                                                   p.27. Text should be
                                                          documents are provided in a consistent manner.                                                                                                            consistent with CTD Q&A
                                                          Further information included in the original change request                                                                                               #4C


CR-20071009-01   Hans van Bruggen, 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 discussion Deferred               Referred to Harmonisation
                 eCTDConsultancy specification v1.2.1     Environmental risk Assessments, using the operations new, append replace            and position                                                          Tasforce
                 B.V.                                     and/or delete.
                                                          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 in       Nov-07 Best Practice guide written for review   Accepted - refer to   Feb-08 Present guidance     Andrew to distribute
                 GSK                                      parallel and affect the same document?                                              and approval                                    eCTD Interlinking     for consideration by eCTD   current documents. Get
                                                                                                                                                                                              Group                 Interlinking Group          comments and consider
                                                                                                                                                                                                                                                inclusion of general
                                                                                                                                                                                                                                                principles/guidance in
                                                                                                                                                                                                                                                harmonised eCTD
                                                                                                                                                                                                                                                guidance. Include details
                                                                                                                                                                                                                                                of particular
                                                                                                                                                                                                                                                scenarios/use cases.
CR-20080129-01   Geoff Williams,   EU M1 stylesheet       The current stylesheet displays the full structure of the Module 1, whether the                                                     Rejected              None
                 Roche                                    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.
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.
                                                                                   EU eCTD Specification Change Requests
      #             Requestor          Specification                                        Description                                                        Comments                        Status                  Action
                                       Component
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 M1 To be implemented in v1.3
                 Roche              v1.2.1                  Please consult regional guidance to submit other versions of PDF.”.               come from EFPIA, clarifying further the use of   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 that application form.
                                                            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 requirement To be included in eCTD v1.3 2008                      Implemented in EU M1      Include acceptance of XML
                                                            to provide a table as a file under 1.0 Cover Letter that keeps track of the                                                      v1.3                      as a file format for the Cover
                                                            sequences, when and when they have been submitted. This will allow each          Format and layout of the table to be defined by                           Letter section (1.0) also.
                                                            NCA to know that any „missing‟ sequences are not relevant to them and            eCTD Interlinking Group.                                                  For implementation in v1.3
                                                            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 M1 To be implemented in v1.3:
                 EMEA               v1.2.1                   1.10 Information relating to Paediatrics. The eCTD specification should be                                                        v1.3                 Amend specification and
                                                             updated in line with the new CTD structure.                                                                                                            stylesheet accordingly
 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  PMF 2nd step is currently a
                 Schwarz            specification, Appendix Plasma Master File (PMF). Following the centralised authorisation of the PMF interim guidance on which submission type to          eCTD Interlinking    type II variation. In the new
                 CSL Behring AG     1 "Envelope Element      the PMF 2nd Step Procedure must be performed. In this 2nd Step Procedure, use.                                                    Group                regulation this will be a type
                                    Description", therein    the PMF certificate must be submitted for each product in order to make the                                                                            IB variation (possibly IA). A
                                    element = submission link between PMF and the product's marketing authorisation. According to the                                                                               dedicated submission type
                                    and attribute = type (p. "Guideline on Plasma Master File (PMF) And Vaccine Antigen Master File                                                                                 for PMF 2nd step is
                                    10)                      (VAMF) “Second Step”" this is NOT a variation submission.                                                                                              considered not to be needed
                                                             If this is done for an existing eCTD, there is no adequate submission type                                                                             at this time, certainly not
                                                             defined in the Module 1 Specification to describe this submission.                                                                                     until the new variation
                                                             Recommendation: Define an additional valid submission type for a PMF 2nd                                                                               regulation is in force and it is
                                                             Step Submission, such as "pmf-2nd-step".                                                                                                               clear what submission type
                                                                                                                                                                                                                    a PMF 2nd step is. In the
                                                                                                                                                                                                                    meantime, produce
                                                                                                                                                                                                                    guidance for applicants
                                                                                                                                                                                                                    detailing how to use the
                                                                                                                                                                                                                    eCTD format both for the
                                                                                                                                                                                                                    PMF itself and for the 2nd
                                                                                                                                                                                                                    step in the MAA. This
                                                                                                                                                                                                                    guidance should be
                                                                                                                                                                                                                    produced by EMEA by end
                                                                                                                                                                                                                    2008.
                                                                               EU eCTD Specification Change Requests
       #           Requestor          Specification                                     Description                                                      Comments                      Status   Action
                                      Component
  CR-20080514    Kevin Wing,     EU Module 1            The example provided for the application number element description on page      Refer to eCTD Interlinking Group for discussion Open   Complete the survey for MS
                 eCTDConsultancy Specification v1.2.1   9 of the guidance is in the format of an EMEA Marketing Authorisation            and drafting of Q&A on what is expected in that        on requirements for
                                                        Number i.e. EU/1/00/150/001 and not an EMEA Procedure Number such as             field. Draft survey for MS on requirements for         application/procedure
                                                        EMEA/H/C/XXX/X/XX.                                                               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 would                                                               appropriate requesting a
                                                        only be assigned upon approval and would also be strength-specific). This is                                                            change to the way
                                                        supported by the explanation provided on page 14 of the EMEA‟s recently                                                                 application numbers are
                                                        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, produce
                                                        EMEA/H/C/XXX/X/XX.                                                                                                                      associated business
                                                        And add a clarification to the description that the number required for this                                                            guidance on how each
                                                        value is the procedure number.                                                                                                          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-20080514-01     Anne Mieke    EU Module 1            Since this information is mandatory in the cover letter, variation and renewal   Refer to eCTD Interlinking Group for discussion Open   Complete the survey for MS
                    Reijnders,   Specification v1.2.1   application form and is useful for retrieving information from the eCTD          and drafting of Q&A on what is expected in that        on requirements for
                 eCTDConsultancy                        lifecycle it would be beneficial to add the Marketing Authorization Numbers to   field. Draft survey for MS on requirements for         application/procedure
                                                        the EU M1 envelope information                                                   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.
                                                                                  EU eCTD Specification Change Requests
       #            Requestor           Specification                                      Description                                                           Comments                           Status                  Action
                                        Component
 CR-20080514-02   Kevin Wing,     EU Module 1             The EU Module 1.2.1 specification only includes instructions relating to 1.3.1        CR originator to draft a proposal for the           Open                    CR originator to draft a
                  eCTDConsultancy Specification v1.2.1    SPC, Labelling and Package Leaflet identifiers and Language/Country Codes             information, to be included in the next version                             proposal for the information,
                                                          in the context of document filenames/folder paths. This information is also           of the specification.                                                       to be included in the next
                                                          required as XML metadata and this change request is to update the                                                                                                 version of the specification.
                                                          specification to clarify this requirement.
CR-20080514-03       Anne Mieke    EU Module 1            Since sequence numbers do not have to be used in sequential order it would            The Cover Letter and tracking table if            Rejected                 None
                      Reijnders,   Specification v1.2.1   be beneficial to add the submission date back into the EU M1 envelope                 appropriate should be used to track the date - it
                  eCTDConsultancy                         information.                                                                          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 a                                                          Implemented in EU        Delete criterion
                                   Criteria               dpi of more than 300. The ETICS testing demonstrated that it does not                                                                   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        Change reference
                                   Criteria               incorrect as it is ICH Q&A 36 - change reference.                                                                                         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        Change EU criterion #18
                                   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 and include comment and
                                                          leaf or node extension 'title' attribute is not empty‟. #18 states „If the value of   included a statement to indicate that this is not                            reference to ICH criterion
                                                          the operation attribute is delete,……title is not required…..Consistency should        consistent with the ICH criterion #20.                                       #20
                                                          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.

 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
                  eCTDConsultancy Specification v1.2.1    ago and has been presented/discussed at conferences, implemented by          which has been improved and is robust with EU Q&A
                                                          some vendors and is included as a term in the EMEA‟s Q&A Relating to         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 the sequence, but to indicate that application
                                                          EU M1 eCTD guidance describes use of the related sequence element to         number is used in addition. Dependency on CR-
                                                          groups eCTD sequences into 3 Regulatory Activities (an MAA, a technical      20080514 and the drafting of guidance for use
                                                          variation and a labelling change variation).                                 of and requirements for application numbers by
                                                                                                                                       all agencies.
                                                          In the afore-mentioned EMEA Q&A document, it is the Application Number
                                                          (procedure number) that is described as the “envelope element which is used
                                                          to group together submissions relating to a particular regulatory 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?
                                                                                EU eCTD Specification Change Requests
       #           Requestor          Specification                                     Description                                                         Comments                           Status                  Action
                                      Component
CR-20080514-05     Anne Mieke    EU Module 1             The application number element description on page 9 of the guidance states See CR-20080514-04 -guidance to be                        Open                    Complete the survey for MS
                    Reijnders,   Specification v1.2.1    that this is the “number assigned to the application by the receiving agency”. produced.                                                                      on requirements for
                 eCTDConsultancy                         Given the explanation provided on page 14 of the EMEA‟s recently released                                                                                     application/procedure
                                                         Q&A on eCTD Implementation (7th February 2008) we presume that for                                                                                            number, and use of this
                                                         Centralised Submissions, the EMEA procedure number is meant here (see                                                                                         element. Once results have
                                                         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 definitions                                                                                change to the way
                                                         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, produce
                                                         Could the TIGes provide feedback/guidance on the definition of the                                                                                            associated business
                                                         Application Number element for MRP, DCP and National Procedures.                                                                                              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 which Article 61(3) exists as a submission type in the             Rejected
                 Schwarz, CSL      v1.3                  are registered under the Central Procedure and the Mutual Recognition        EU M1 specification v1.3
                 Behring AG                              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.

  CR-20080703    Andrew Marr       EU M1 Specification   The list of submission types included in the eCTD Module 1specification v1.3     As part of the creation of EU Module 1, v1.3           Accepted - refer to   Discuss again in eCTD
                 (EFPIA)           v1.3                  does not include Repeat Use Procedure. What submission type should be            and in conjunction with the development of the Q&A                           Interlinking to confirm that
                                                         used for this submission?                                                        eCTD in MRP/DCP Best Practice document                                       it was agreed that this
                                                                                                                                          consideration was given to the creation of
                                                                                                                                                                                                                       should not be includd as a
                                                                                                                                          „Repeat Use Procedure‟ as a specific
                                                                                                                                          submission type. After deliberation, this was
                                                                                                                                                                                                                       submission type in the next
                                                                                                                                          not accepted. However, the Best Practice                                     version of EU M1
                                                                                                                                          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‟.
                                                                                 EU eCTD Specification Change Requests
      #             Requestor         Specification                                       Description                                                        Comments                      Status           Action
                                      Component
CR-20080703-01   Andrew Marr       EU M1 Specification   The list of submission types included in the eCTD Module 1specification v1.3  As part the development of the eCTD in         Accepted - refer to   Discuss again in eCTD
                 (EFPIA)           v1.3                  does not include a specific submission type for a change of the Reference     MRP/DCP Best Practice document it was          Q&A                   Interlinking to confirm that
                                                         Member State in MRP. What submission type should be used for this             agreed that „Change of RMS‟ would utilise an                         it was agreed that this
                                                         submission?                                                                   existing submission type and that a Q&A should
                                                                                                                                                                                                            should not be included as a
                                                                                                                                       be prepared to this effect.
                                                                                                                                       The submission type that should be used is
                                                                                                                                                                                                            submission type in the next
                                                                                                                                       „supplemental-information‟ and the submission                        version of EU M1
                                                                                                                                       description should be „Change of Reference
                                                                                                                                       Member State‟
 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
                 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 table MRP and DCP on page 45.
                                                                                                                                                                                                            XML on p.45
                                                         is not included in the folder m1/eu/10-cover/common.
                                                         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 IB Accepted       Refer to EMEA post-
                 GSK               v1.3                  dossiers – all CHMP members should get an electronic copy of everything,            variations are split by NeeS and eCTD. For                     approval copy requirements
                                                         including Type IA/IB variations – otherwise future lifecycle operators will be      NeeS, they stay as they are. For eCTD, the                     for change to text.
                                                         invalid.                                                                            requirements for Type IA and IB variations
                                                         The current copy requirements do not differentiate between eCTD and NeeS.           mirror those for Type II – i.e. “Other CHMP
                                                         For Type IA and IB variations, only the Rapporteur requires 2 electronic            members: 1 electronic copy”.
                                                         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
                                      Component
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   Accepted - refer to   Discuss and agree in eCTD    Identified as a hurdle for
                 GSK               Practice Guidance   preferring to centralise electronic dossier production, or following the       form, a single „common‟ English language cover eCTD Interlinking     Interlinking group           eCTD implementation.
                                                       preferred „Comprehensive model‟ for eCTD in MRP/DCP must get a cover           letter is acceptable in all MS.                Group                                              Cover letter is not
                                                       letter translated into all European languages before building the dossier. For
                                                                                                                                                                                                                                        covered by legislation,
                                                       submissions requiring an application form, this is unavoidable, since the form
                                                       contains details of the MAH, and local contacts etc. However, for follow up
                                                                                                                                                                                                                                        but nevertheless some
                                                       measures, or simple administrative submissions, the requirement to get a                                                                                                         MS have requirements
                                                       cover letter translated up to 23 times is onerous and does not add value to                                                                                                      for local laguage
                                                       the dossier (NB the rest of the content is likely to be in English). Could a                                                                                                     versions. HMA to try to
                                                       „common‟ English language cover letter be used for such submissions?                                                                                                             persuade individual
                                                                                                                                                                                                                                        agencies to relax
                                                                                                                                                                                                                                        requirements for a cover
                                                                                                                                                                                                                                        letter in the local
                                                                                                                                                                                                                                        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
 CR-20080909     Leigh Sandwell,   eCTD Guidance       Current guidance requires that statements justifying absence of data in the   Recommend that empty Module 1 Sections do       Accepted - refer to   Discuss further in eCTD      Approach to M1 is
                 Pfizer                                eCTD should be provided in the QOS, non-clinical and clinical overviews, as   not require a justification statement to be     eCTD Interlinking     Interlinking Group. If       different than for other
                                                       applicable, and that no placeholder documents are required in the eCTD        included in each section and the Q&A            Group                 acceptability of no          modules, as M1 should
                                                       structure. The guidance should be updated to clarify how to deal with empty   document is updated to reflect Module 1.
                                                                                                                                                                                                           placeholder documents in     always be populated
                                                       sections of Module 1 and any potential justification that may be required.
                                                                                                                                                                                                           M1 is confirmed, update      (even with 'not
                                                                                                                                                                                                           Q&A, specification and       applicable' statements) as
                                                                                                                                                                                                           existing guidance as         a legal requirement.
                                                                                                                                                                                                           applicable to confirm that   Another proposal is that
                                                                                                                                                                                                           any M1 justifications        only justifications should
                                                                                                                                                                                                           required should be           be required - simple
                                                                                                                                                                                                           submitted as an attachment   statements of not
                                                                                                                                                                                                           to 10 Cover Letter.          applicable should be
                                                                                                                                                                                                                                        included in the cover
                                                                                                                                                                                                                                        letter. Revisit this
                                                                                                                                                                                                                                        discussion as currently no
                                                                                                                                                                                                                                        agreement.
                                                                               EU eCTD Specification Change Requests
      #             Requestor          Specification                                    Description                                                     Comments                        Status                 Action
                                       Component
CR-20080909-01   Dietmar Boecker,   eCTD Guidance        Guidelines on the submission of the EU-RMP require a stand-alone format of                                                     Accepted               Refer to EMEA eCTD
                 Bayer Schering                          the document including all annexes to be located in eCTD Module 1.8.2. This                                                                           Business Team for
                                                         is in contradiction to the ICH eCTD requirements, that mandates a different                                                                           discussion and confirmation,
                                                         location for most of the annexes.
                                                                                                                                                                                                               and amend all guidance
                                                         In section 4.4 of the EU-RMP guideline EMEA/CHMP/96268/2005 it is
                                                         outlined that the EU-RMP "should be provided (...) in a stand-alone format
                                                                                                                                                                                                               documents as 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   Draft an eCTD Q&A to
                 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                   detail a proposal for all
                                                         renewals is available.                                                        assigned to specific CTD-defined locations then                         additional documents for
                                                                                                                                       they should be included in 1.2 Application
                                                                                                                                                                                                               variations and renewals in
                                                                                                                                       Form. These might include declarations,
                                                                                                                                       certificates, justifications etc. Where possible,
                                                                                                                                                                                                               the eCTD, consistent with
                                                                                                                                       they should be organised according to the                               the CTD Q&A 4c (must
                                                                                                                                       Annexes for the Application Form for new                                include information on
                                                                                                                                       products (Annexes 1 to 22). Where documents                             renewals also)
                                                                                                                                       cannot be assigned to one of the annexes then                           Propose to amend EU M1
                                                                                                                                       it is appropriate to place them after the                               specification in next version
                                                                                                                                       annexes. The „Additional Data‟ section of                               to also reflect the CTD
                                                                                                                                       Module 1 should not be used except for country-
                                                                                                                                                                                                               Q&A.
                                                                                                                                       specific information.
                                                                                                                                                                                                               The eCTD Q&A, detailing
                                                                                                                                       The EU M1 specification should therefore be
                                                                                                                                       amended in the next version to reflect this, and                        the approach, should be
                                                                                                                                       a Q&A is required to confirm this, and also to                          referred to in the meantime.
                                                                                                                                       confirm that the same approach should be
                                                                                                                                       taken for renewals.
                                                                                  EU eCTD Specification Change Requests
    #            Requestor          Specification                                          Description                                                        Comments                       Status   Action
                                    Component
CR-20081008   Andrew Marr, GSK eCTD specification         The guidance just issued by QRD regarding production by the applicant of the        Dec 08: EMEA meeting held to discuss issue - Accepted   EMEA to revise eCTD
              (EFPIA)          v3.2                       PDF for final labelling is incompatible with the eCTD and will lead to              conclusion that requirements for EMEA PDFs              guidance to reflect the
                                                          duplication of effort.                                                              arise from the EMEA EPAR publication                    inconsistency, and advise
                                                          In the longer term EMEA must align their requirements and if there is               process, and eCTD filenaming requirements
                                                                                                                                                                                                      that, until further notice, the
                                                          business logic for the filename as per the EPAR proposed name then an EU            have a different purpose and support a different
                                                          specification change may be justified with the inclusion an appropriate             proess (review) and therefore requirements
                                                                                                                                                                                                      eCTD filenaming
                                                          filename that meets ICH general filename requirements.                              cannot be aligned until Q3 2009 when the                convention should be used
                                                                                                                                              EMEA publication process is re-designed. This           for the product documents
                                                          In the short-term there is an urgent need for clarification as to how an            conclusion was not redily accepted by industry -        in the eCTD, and at the time
                                                          applicant can submit product information inside and outside the eCTD, for all       either alignment must be sought, or at least            of publication of the EPAR,
                                                          submission types without duplication of effort or risk of failure to validate or    clear guidance should be provided as to how to          a separate folder outside the
                                                          accept                                                                              manage in the meantime, adn a clear plan for            eCTD should be submitted,
                                                                                                                                              resolution should be presented by EMEA
                                                                                                                                                                                                      containing a zip file with all
                                                                                                                                                                                                      of the translated product
                                                                                                                                                                                                      information PDFs (exact
                                                                                                                                                                                                      copies of the final files
                                                                                                                                                                                                      inside the eCTD), observing
                                                                                                                                                                                                      the EMEA filenaming
                                                                                                                                                                                                      convention. These files are
                                                                                                                                                                                                      used for publication only,
                                                                                                                                                                                                      and the files in the eCTD are
                                                                                                                                                                                                      used for archiving and
                                                                                                                                                                                                      lifecycle. (In non-eCTD
                                                                                                                                                                                                      electronic submissions, the
                                                                                                                                                                                                      EMEA filenaming
                                                                                                                                                                                                      convention should be
                                                                                                                                                                                                      observed).
                                                                                                                                                                                                      Plan further meetings to
                                                                                                                                                                                                      address the alignment.
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       Open
              Neurauter, Etedo                            checksum in the provided index-md5.txt. Guidance is given by the EMEA to            additional issue: “The checksum of the
                                                          provide this checksum in the cover letter, however, the possibility to verify the   index.xml should be calculated by a validation
                                                          MD5 with the EURSvalidator is not given.                                            tool and compared with the checksum provided
                                                          Authorities not using the EURSvalidator perform checks with tools verifying         in the index-md5.txt.” In case of invalidity the
                                                          the overall checksum. We received responses from clients that submissions           recommended severity should be A.
                                                          are rejected due to invalid values in the index-md5.txt. However this issue is
                                                          not part of the EU Validation Crieria.
                                                          In case of MRP/DCP we encounter troubles that submissions are accepted
                                                          only in regions the EURSvalidator is used.

				
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