eu ectd and nees validation criteria v6 printesubmission.ema.europa.eu/tiges/docs/eu ectd and... ·...

EU eCTD and NeeS ValidationEU eCTD and NeeS Validation Criteria Webinar

TIGes Harmonisation GroupTIGes Harmonisation Group

13th July 2012

1European Update on Validation of eCTD &

NeeS submissions, July 2012

Presenters of the day from TIGes H i ti GHarmonisation Group

l ( )Alastair Nixon (EFPIA)

Klaus Menges (DE)aus e ges ( )

Manuela Copier (EFPIA)

Mickel Hedemand (DK)

Jaspreet Singh (EMA)Jaspreet Singh (EMA)

Karin Gröndahl (SE)



Why change?Why change?

h i ifi i ( )• Changes in EU specification (EU m1 v1.4.1)

• Changes at ICH level, need to be reflected in C a ges at C e e , eed to be e ectedEU

• Lack of harmonisation between vendors• Lack of harmonisation between vendors, interpretation of the rules themselves

• Quality of dossiers received by agencies still needs to improve

• Desire to automate the validation process



eCTD Criteria Changes

These changes also applied toThese changes also applied to equivalent NeeS criteria if applicable



DTDs MOD files and StylesheetsDTDs, MOD files and Stylesheets• ‘Currently acceptable’ is now a direct comparison with theCurrently acceptable is now a direct comparison with the

published checksum

• References to these from index xml and eu‐regional xml mustReferences to these from index.xml and eu regional.xml must go to the location as specified in the DTD/MOD/Stylesheetcheck itself

• Uniform Resource Identifiers (URIs) – links to DTDs, Stylesheets etc must be URIs (see later slide on hypertext y ( yplinks)

• 2 new criteria for DTDs – checks again preceding and g p gsucceeding sequences, to check when sequences are submitted out of order – see next slide



DTD Criterion Scenario 1DTD Criterion Scenario 1

Sequence 0004 DTD 1.3

S 0006 DTD 1 4



Criterion 1.4 ≥ preceding sequence1.3 = 1.3

Criterion 1.5 ≤ succeeding sequence1.3 < 1.4





S 0006 DTD 1 4



Criterion 1.4 ≥ preceding sequence1.3 not ≥ 1.4

Criterion 1.5 ≤ succeeding sequence1.3 < 1.4




Sequence 0004 national, not in lifecycle


S 0006 DTD 1 3



Criterion 1.4 ≥ preceding sequence1.4 ≥ 1.3

Note: Preceding sequence in this i 0003 th t l h ld k

Criterion 1.5 ≤ succeeding sequence1.4 ≤ 1.3

case is 0003, the tool should work backwards (or forwards) to the next sequence present



EnvelopesEnvelopes

• Added check for procedure type : if procedure type is 'mutual‐recognition' or 'decentralised‘, there must be one or more country specific envelopes (not EMEA)more country specific envelopes (not EMEA)

• Similarly for procedure type is ‘national’ – only one envelope allowedallowed

• New leaf/envelope consistency rules:

• Sequences with new/append/replace leaves under country specific elements must have that country in the envelope ( /f il)(pass/fail)

• Sequences with ‘delete’ leaves – same rule, but BP only to ll f l f iallow for removal of incorrect content



Files/FoldersFiles/Folders

• Acceptable formats – removed ‘rtf’ in line with EU m1 v1.4.1

• Valid characters – clarification, must be tested on file names themselves, not xlink:hrefs in XML

• File naming in ASMF dossiers – ‐rp and ‐ap now recommended as suffixes in both eCTD and NeeS (ASMF Guidance still to be updated, it recommends prefix)

• Multiple hyphens allowed in –var component of name



Files/Folders Naming WorksheetFiles/Folders Naming Worksheet

• Additional tab – Files and Folders Q&A.

• Modules 1, 2 & 3 – no additional folders beyond specified structure allowed

• Exception ‐ sections m3.2.A and m3.2.R

• Module 4 ‐ additional folders are optional.

• Module 5 ‐ additional folders are required for all sectionsModule 5 additional folders are required for all sections apart from m5.2, m5.3.6 and m5.4. Optionally, additional folders below the specified structure are also allowed.



Files/Folders Naming Worksheet ‐Examples

• 0000/ 1/ /10 / / df• 0000/m1/eu/10‐cover/emea/emea‐cover.pdf• 0000/m1/eu/10‐cover/emea/addendum/emea‐cover‐

addendum.pdfFolder not allowed

• 0000/m4/42‐stud‐rep/421‐pharmacol/4211‐prim‐pd/studyfolder/report1.pdf

Folder not allowed

p y p p

• 0000/m5/53‐clin‐stud‐rep/531‐rep‐biopharm‐stud/5314‐bioanalyt‐analyt‐met/report1 pdf Subfolder mandatoryanalyt met/report1.pdf

• 0000/m5/53‐clin‐stud‐rep/531‐rep‐biopharm‐stud/5314‐bioanalyt‐analyt‐met/report 1/report1.pdf

• 0000/m5/53 clin stud rep/531 rep biopharm stud/5314 bioanalyt

Subfolder mandatory

• 0000/m5/53‐clin‐stud‐rep/531‐rep‐biopharm‐stud/5314‐bioanalyt‐analyt‐met/report 1/appendix/report‐appendix.pdf



PDF FilesPDF Files

d l d h l ll• More details on security settings , and m1.2 now has its own rule to allow for eAF

• Additional criterion to test for corrupted files• Additional criterion to test for corrupted files

• PDF versions 1.4, 1.5, 1.6, and 1.7 now all allowed

Method of testing PDF ersion specified– Method of testing PDF version specified

• Hypertext links – only links that work within the software being used to view the dossier are testedview the dossier are tested

– Excludes mail links (open e‐mail client)

– Excludes web links (open web browser)Excludes web links (open web browser)

• Bookmark criterion now split – bookmarks present, they are visible, no bookmarks, page only



Hypertext LinksHypertext Links

i i h k li f li k• New criterion – checks compliance of links as per configuration specified in ISO 32000‐1:2008– Backslashes are not allowed

• Background– Links with backslashes will work on Windows fileLinks with backslashes will work on Windows file systems:

• \\MyDrive\Testing\eCTD\Samples\0000\util\dtd

– Links with forward slashes will work in all operating environments (egSmart Phones, Tablets):

• //MyDrive/Testing/eCTD/Samples/0000/util/dtd



‘Y’ CriteriaY Criteria

• Text changed:

Test marked with “Y” needs the relevant former sequences for the specific criterion to be present for the result to be fully reliable. If these sequences are not present when testing, any FAIL results for these criteria should be interpreted carefully.

When reporting a 'Fail' for these 'Y' criteria, validation tools should also report the specific missing sequences that are related to the 'Fail'.



‘Y’ Criteria ‐ Examplep11.6 leaf attributes The file referenced by the cross

reference (xlink:href) must exist in the same or a previously submitted

ithi th CTD

P/F Y The link within the XML leaf element is valid, i.e the target exists

sequence within the same eCTD application

• If a cross reference is not found, the validation report should present this as a ‘Fail’ but also specify whichshould present this as a Fail , but also specify which sequence was referred to, and whether or not the sequence was present at the time of doing the testsequence was present at the time of doing the test

Sequence was present

Sequence was not presentpresent not present

Reliable FAIL – targeted document did not exist

Unreliable FAIL – targeted document may exist, but this cannot be tested because sequence is missing



Specific NeeS Criteria Changes



Table of ContentsTable of Contents

• Module TOCs – clarification – links must only go to content within that module

• Original criterion: “within the respective mX‐folder”, now “Links from a module TOC must not be directed to content outside of that module ”outside of that module..

• New rule on paths in TOC links ‐ The path in hyperlinks and bookmarks from ToC files sho ld ne er contain the fo r digitbookmarks from ToC files should never contain the four digit NeeS folder.



Hypertext Links Containing the Four Digit NeeS Folder

Link ../0000/m1/eu/10‐cover/be/be‐cover.pdf resolves OKcover/be/be cover.pdf resolves OK

Once loaded into the agency’s system:

Link ../0000/m1/eu/10‐cover/be/be‐cover.pdf broken, or could point to the wrong letter (incould point to the wrong letter (in 0000)! .....would need to be ../0003/m1/eu/10‐cover/be/be‐cover pdf but should becover.pdf, but should be “m1/eu/10‐cover/be/be‐cover.pdf”



NeeS Acceptable FormatsNeeS – Acceptable Formats

• Criterion 2.2 – Current criteria – refers to ICH eCTD Specificationp

– Revision – PDF only (refers to TIGes Harmonised NeeS Guidance)NeeS Guidance)



NeeS Folder and File NamingNeeS – Folder and File Naming

• No changes to criteria

• However, note, specific new folder rules in ‘Files and Folders Q&A’ sheet, detailed in ‘File‐Folder Structure & Names’ sheet are Pass/Fail for NeeS



Key Points for Vendors of eCTD/ NeeS Toolsy /

• DTD/stylesheet checks – all P/F. If you market a tool today that inserts the wrong checksum, or does not use the forward slashes in XML references to DTDs, MOD files etc, all eCTDs produced in this tool will fail from December 1st (P/F)

Li k i N S TOC t t t i th f di it b i i b• Links in NeeS TOCs must not contain the four digit submission number (e.g. ‘0000’). If you market a tool today that includes the four digit number in TOC hypertext links, this needs to change, otherwise your tool will be producing invalid NeeS (P/F)

• If you market software that is supplied with templates for NeeS folder structure the new rules on allowed folders will potentially make all NeeSstructure, the new rules on allowed folders will potentially make all NeeS dossiers made with an existing template fail (P/F)

• Hypertext links or bookmarks must not have backslashes in the path. IfHypertext links or bookmarks must not have backslashes in the path. If you market a tool today that inserts Windows style links into PDFs for submission in the EU, all links will fail the test (BP). This may be changed to a pass/fail in the future for TOC files and the XML backboneto a pass/fail in the future for TOC files and the XML backbone.



LastlyLastly...

• The eCTD criteria have been updated once more, look out for the most recent proposal p pcoming soon to the eSubmission web site:

v4.1 July‐2012

Typo corrections on criteria 3 3 3 5 and 16 3 Also the description ofTypo corrections on criteria 3.3, 3.5 and 16.3. Also, the description of the * ("Y"‐criteria) is further clarified.



Questions



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