eCTD : EMEA Experiences

1
eCTD EMEA Experiences

• Evdokia Korakianiti Ph.D
• Scientific Administrator
• Quality sector
• Pre-Authorisation Human Medicines Unit
• EMEA

2
Presentation overview

• eCTD Implementation Strategy at EMEA-Key
  Milestones
• Current Status EMEA
• eCTD Statistics EMEA
• Electronic Submission Available Guidance
• Frequently asked eCTD related questions
• Key Messages for Industry
• Conclusions

3
eCTD Implementation Strategy at EMEA- Key
Milestones

• From 1 July 2008
• The EMEA accepts electronic-only submissions,
  either in eCTD format or non-eCTD format (eCTD is
  the recommended electronic format), with no
  additional requirement for paper copies
• This applies to all applications (new and
  existing) and all types of submissions to the
  EMEA in the context of the centralised procedure
  (e.g. new applications, supplementary
  information, variations, renewals).
• Rapporteurs and CHMP members may, however, still
  have paper-copy requirements at this point.

4
eCTD Implementation Strategy at EMEA- Key
Milestones

• From 1 January 2009
• The EMEA strongly recommends electronic-only
  submissions, either in eCTD or non-eCTD format
  (eCTD is the recommended electronic format)
• Paper will be an exception to the general
  e-format recommended for any application. This
  will apply to all applications (new and existing)
  and all submission types.
• Rapporteurs and CHMP members will not receive
  paper copies from this date.

5
eCTD Implementation Strategy at EMEA - Key
Milestones

• From 1 July 2009
• The EMEA will strongly recommend eCTD-format
  electronic-only submissions.
• Paper and other electronic formats will be an
  exception to the general e-CTD format recommended
  for any application.
• This will apply to all applications (new and
  existing) and all submission types.
• Rapporteurs and CHMP members will not receive
  paper copies or other electronic formats from
  this date.

6
Mandatory eCTD for the Centralised Procedure

• Although electronic-only submission for the
  Centralised Procedure cannot be mandated due to
  lack of legislative basis, it is possible to
  mandate the format of the electronic-only
  submission if received
• Hence new milestone in EMEA eCTD Implementation
  Strategy
• Published December 2008

7
Mandatory eCTD New Milestone

• From 1 January 2010
• The EMEA will mandate the use of the eCTD format
  for all electronic-only submissions for all
  applications (new and existing) and all
  submission types.
• Rapporteurs and CHMP members will not receive
  paper copies or other electronic formats.
• NEES
• In addition, until 1 January 2010, any non-eCTD
  electronic submission provided in the context of
  the Centralised Procedure must also comply with
  the EMEAs new specific guidelines for non-eCTD
  electronic submissions. All other current
  guidance remains in force.

8
Mandatory eCTD Implications

• Non-eCTD format electronic submissions will be
  rejected
• Paper-only submissions would be accepted as an
  alternative, but
• Will lead to significant handling and review
  issues, as all EMEA processes will be engineered
  towards electronic submissions

9
Current Status EMEA

• Number of eCTDs are increasing exponentially at
  EMEA
• European Review System for eCTDs (EURS) is used
  by the entire agency as the sole tool for the
  handling and review of eCTD and NEES submissions
  received by the Agency
• Although still the majority of eCTDs are new
  applications, the last 6 months have seen an
  increase in the number of converted eCTD
  baselines received for authorised products with
  ongoing regulatory activity

10
eCTD Statistics EMEA

• 988 eCTD submissions received since 1st July 2008
• 228 products currently managed in eCTD format
  (approximately half of all CP active products)
• October 2008
• 573 electronic submissions received by EMEA
• 112 of those eCTD
• November 2008
• 561 electronic submissions received by EMEA
• 63 of those eCTD
• December 2008
• 787 electronic submissions received by EMEA
• 204 of those eCTD (highest no. received in a
  month so far)
• January 2009
• 485 electronic submissions received by EMEA
• 162 of those eCTD

11
Electronic Submission Available Guidance

• eCTD and electronic submission Statement of
  Intent
• Mandatory eCTD Statement of Intent
• NeeS Implementation Statement of Intent
• QA on eCTD/electronic-only Strategy
• Practical/technical guidance on submitting eCTD
  to EMEA
• Practical guidance on submitting NeeS to EMEA
• All available at
• http//www.emea.europa.eu/htms/human/genguidance/g
  enreg.htm
• Or contact EMEA eCTD_at_emea.europa.eu
• Specific practical guidance on using eCTD for PMF
  and ASMF submission currently being drafted

12
Frequently asked eCTD related questions (as
received by the EMEA)
13
eCTD baseline content

• Q Should only the most current information be
  provided for each heading, or a cumulative
  chronological presentation of the content over
  time in a single leaf element?
• A There is no need for a chronological
  cumulative presentation of the content of the
  dossier. The latest approved information should
  be included in an eCTD baseline submission.
• Q Is it acceptable to exclude information that
  is not current (e.g. for very old products)?
• A It is not acceptable to exclude any
  information from the original dossier unless it
  has been updated by a regulatory process, (e.g.
  variation, line extension etc).
• The information included in 3.P.2 is not subject
  to variations, therefore all the original
  information should be included in the baseline
  plus any additional development studies that have
  been performed during the lifecycle of the
  product

14
Sequence

• Q In the EU eCTD guidance, it is mentioned that
  the first sequence should be 0000. For the
  original MAA this is very clear, but what if an
  application is changed to eCTD after the MAA has
  been granted, e.g. for a type II variation?
• A The first eCTD sequence should always be
  0000, regardless of whether it is an initial MAA,
  variation etc. or baseline.

15
Blank folders

• Q For legacy products not all sections within
  the quality module might have content. Is this
  acceptable?
• A In principle all CTD sub headings should be
  addressed. Statements justifying absence of data
  for specific CTD sections should be provided in
  the relevant Quality overall summary (NTA, Vol.2
  B). Placeholder documents highlighting 'no
  relevant content' should not be placed in the
  eCTD structure

16
eCTD structure- Multiple manufacturers

• Q In section 3.2.P.3 is a single file required
  with multiple bookmarks relating to each
  manufacturing site, or one file per manufacturing
  site?
• A There is no preference. In choosing either
  option the applicant should consider
• How different is the manufacturing process used
  in the sites
• The ease of maintaining this information during
  the lifecycle of the product (e.g. deletion or
  replacement of sites)
• Q Is the optional XML attribute for finished
  product manufacturer useful for the Authorities?
• A Only, if it is manufacturer specific

17
eCTD structure multiple strengths

• Q Do applications need to be structured per
  strength?
• A No. eCTD should be managed at INN level (EU
  harmonisation subgroup decision)
• Q Is it useful to include the strength in the
  XML Dosage Form attribute if most files are not
  written per strength?
• A Only for documents in the dossier that are
  specific to one strength. Metadata cannot be
  changed by the applicant during the product
  lifecycle the meta-data level should be
  future-proof

17
18
CMC XML attributes

• Q EU eCTD CMC guidance offers a range of options
  for CMC XML attributes - are some preferred over
  others? Is it accepted that 3.2 attributes are
  free-text fields that can be used as best decided
  by the applicant?
• A There are no preferred approaches, there is no
  guidance from any region. Attributes are
  free-text fields that can be used as best decided
  by the applicant. Over time when more experience
  is accumulated more guidance could be issued, at
  this point there is not enough experience

19
CMC XML attributes (contd)

• Q Is there a preference for the XML attribute
  entry of the Dosage form? e.g., EU standard term
  or a shorter term? How to handle discrepancies
  in the EU, e.g. 'prolonged release' vs. 'extended
  release'?
• A No preference as long as it is clear

20
CMC XML attributes (contd)

• Q Are CMC XML attributes used for other purposes
  other than providing separate sections?, e.g.,
  referencing, cataloguing sources, database
  queries?
• A Not at the moment. It is intended that in the
  future CMC XML attributes will be used when the
  review tool is linked to the EMEA tracking
  databases but this is long way to go.
• By that time the next version of the eCTD (RPS)
  might be issued, which will be more structured.

21
Filenames

• Q Are ICH eCTD Appendix 4 filenames mandatory in
  Europe?
• A No, they are just highly recommended.

22
APPEND operation

• Q What is the EMEAs view on the use of
  operation attribute APPEND in Module 3 and 2.3?
• A Its best to avoid APPEND, because EMEA
  experience so far shows that it is the least
  understood operation by tool vendors and it is
  the most open to interpretation

23
ASMF in eCTD

• How does the electronic Active Substance Master
  File fit into the eCTD or electronic-only
  submission structure? What if ASMF is in paper or
  NeeS and the product dossier is in eCTD?
• TIGes Harmonisation Subgroup draft eCTD guidance
  (for all procedures) The closed and open part
  of an ASMF should be submitted in the eCTD

24
CEPs- Tables A,B,C

• Ph Eur Certificate(s) of Suitability also appear
  in Module 1.2
• Drug Substance Annex 5.10
• TSE Annex 5.12
• These may be linked from Module 3.2.R
• to point to the same file in the folder directory
• Tables A,B,C need not appear in Module 1.2
• For materials of animal origin

25
Linking- Cross references to other sequences or
eCTDs

• Q Hypertext linking - within the same
  application, how much is really needed in Module
  3?
• A Keep it minimal
• Q Has linking of files across XML folders caused
  confusion for CMC reviewers? e.g., same P.4 file
  linked across 5 excipient folders but all
  pointing to the same file in the folder
  directory?
• A There is no confusion if a review tool is
  used. BUT some MS are not routinely using a
  review tool--gt might be a problem
• Q Will EU accept cross-references to other eCTD
  applications? e.g., for Module 3 information?
• A Currently not, but might be possible with the
  next version of eCTD (still under discussion).

26
Parallel variations

• Q How to handle parallel variations for Module
  3?
• A If the same document is used to support two
  parallel variation, it is acceptable to include
  it only in one submission and the make a
  cross-reference in the other one (in this way the
  document lifecycle is maintained).

27
Validation

• Q Current validation rating is Category B (non
  serious) - will resubmissions be necessary for
  Category B validation rating?
• A No

28
Key Messages for Industry (1)

• Concern at EMEA that the majority of
  electronic/eCTD applications are STILL
  accompanied by a paper copy this is disposed of
  on receipt by EMEA
• Many companies receiving requests for paper from
  NCAs please do not provide paper but instead
  contact EMEA for guidance and resolution
• Limit submissions to one per CD/DVD, clearly
  labelled
• Send DVD in place of multiple CDs (multiple CDs
  lead to handling difficulties)
• Companies should refer to the EMEAs practical
  guidance for detailed information on presentation
  and structure of the eCTD

29
Key Messages for Industry (2)

• Not always sufficiently clear which regulatory
  activity a submission belongs to (correct use of
  application number in PA submissions, related
  sequence, submission description)
• Information relating to multiple regulatory
  activities should not be combined within a single
  eCTD submission (applies particularly to
  FUMs/SOs/PSUR we have seen several submissions
  that combine all these into one sequence)
• EU M1 v1.3 must be used for all applications
• List not exhaustive...if in doubt about any
  aspect of eCTD use, ask EMEA

30
Conclusions

• Implementation of eCTD at an Agency level has
  been successful so far
• EMEA will comply with HMA statement by end 2009
• Still work to do internally regarding deep
  understanding of the eCTD on an operational level
• Work really only just beginning on lifecycle
  management requirements, integration with
  existing systems and further eCTD development
• Learning process for all applicants are
  encouraged to contact EMEA to discuss business
  and technical issues with eCTD will lead to
  better understanding and guidance

31
Acknowledgements

• Claire Holmes
• EMEA eCTD Business Team

32

• Thank you for your attention !