1. An Overview of eCTD for CMC Specialists Dr Martin Moxham June 2010 iRegulatory Ltd, 1 Viewpoint Office Village, Babbage Road, Stevenage, SG1 2EQ, United Kingdom. http://www.i-regulatory.com 1

2. This Presentation Overview of the eCTD –eCTD components –Life cycle management –Building and viewing Best practices for eCTD authoring and publishing Challenges for CMC specialists 2

3. Part 1: Overview 3

4. About eCTD (1) eCTD is the electronic version of CTD Specification developed by ICH (Topic M2) in parallel with Topic M4 (CTD) There is no difference between the two in terms of scientific, technical and clinical content Specification was finalised in November 2003 Regional differences in implementation 4

5. About eCTD? (2) A standard electronic format for sending data from the applicant to the regulatory authority Vendor and system independent, in terms of both creation and use –in theory! –interoperability problems have occurred –collaborative interoperability studies (ETICS I, II and III) have been done to address these issues (http://www.iriss-forum.org/)http://www.iriss-forum.org/ eCTD ApplicantRegulatory authority (built using any tool/method capable of producing a valid eCTD) (viewed using any software tool capable of viewing a valid eCTD) 5

6. eCTD Organisation Components to an eCTD: –Scientific and technical contents multiple files, mainly PDF –Folder structure follows the CTD heading structure –XML index files (backbones) main (M2-5) and regional (M1, main index contains a link) provides an index to the contents supports life cycle management functionality –Study Tagging Files (US only) provides additional descriptive information (meta data) on studies included in Modules 4 and 5 6

7. Scientific and technical content Multiple files, usually PDF Granularity as per ICH M4 annex (as for the paper CTD) –“A document is defined for a paper submission as a set of pages, numbered sequentially and divided from other documents by a tab” –“A document can be equated to a file for an electronic submission” 7

8. Content Granularity In general, ICH M4 specifies coarsest granularity that is considered acceptable –Often, the applicant has the option to choose a finer granularity In a full CTD –Module 2 will be broken down into at least 18 discrete documents –Module 3 will be broken down into 50+ discrete documents –Module 4 study reports are presented as one discrete document per report –Module 5 study reports are broken down into at least three discrete documents per report (a “synopsis”, a “body” and one or more “appendix” documents) FDA requires fine granularity for clinical study reports 8

9. Granularity Module 2 9

10. Granularity Module 3 10

11. XML backbone function Effectively an “inventory” or “catalogue” of the submission contents Displays as a hyperlinked table of contents for the submission Contains version control information to support life cycle management 11

12. XML backbone structure Hierarchical structure with “heading elements” for each CTD section –As per CTD –Elements for CTD sections where multiplicity is allowed e.g. 2.3.S, 3.2.S, 2.3.P, 3.2.P are differentiated by attributes “Heading elements” contain “leaf elements” Typically (but not always), there is one leaf element for each file in the eCTD sequence 12

13. eCTD Life Cycle Management An eCTD consists of discrete “sequences” The initial submission is sequence 0000 Subsequent amendments and supplements are provided as sequences 0001, 0002, 0003… etc –each sequence contains changes only; not the full CTD 13

14. eCTD Life Cycle Management Life cycle management uses the leaf element attributes, as follows: –ID: a identifier for the leaf element (unique in the index file) –operation: “new”, “replace”, “append”, “delete” –modified-file: A pointer (by ID) to the leaf element in the previous sequence that is the “target” for the operation not applicable to the “new” operation –xlink:href: the relative file path to the relevant document in the current sequence not applicable to the “delete” operation 14

15. Hyperlinking is degraded by life cycle management 00000001 Replace Hyperlinks delete 15

16. Building and viewing eCTDs Specialist tools are used for eCTD publishing –typically, these are integrated with document management systems It is possible to use a web browser with Adobe Acrobat installed to view individual sequences in isolation Review tools provide an integrated view of all sequences 16

17. Part 2: Best Practices 17

18. eCTD practicalities: General Some challenges with eCTD are common to paper CTD, namely: –Employing a robust and verifiable process for document authoring and version control –Complying with the ICH M4 Annex regarding granularity –Inserting the right document in the correct location in the submission –Ensuring that documents are well-formatted, complete and legible Old legacy reports can be particularly problematic 18

19. eCTD practicalities: General Some additional issues are specific to eCTD: –Ensuring adequate hyperlinking and bookmarking for ease of navigation –Choosing attributes appropriately e.g. substance, product-name, dosageform, manufacturer etc –File naming –Font issues –Text versus scanned PDF 19

20. Managing authoring and dossier content Operate to “Good Regulatory Practice” –Procedures to ensure information authenticity and the ability to confirm origin of all information included in the dossier –Rigorous procedures for internal review and approval Benefits include improved dossier quality, resulting in fewer questions and fewer delays in assessment 20

21. Controlled documentationCTD / eCTD submission GMP (manufacturing and controls) GLP (non-clinical safety evaluation, analytical methods and validation) GCP (clinical research) Summary documentation (Mainly Module 1-3) 21

22. Have you ever experienced the pain…? 22

23. Document identification and version control (1) Best practice suggestions: Use a document management system –Allows far greater control and traceability than a file system –BUT it is still possible to make mistakes The wrong document or wrong version can still be checked in –Control risks by ensuring that read/write access is restricted to appropriately trained staff who require access Always check the final submission carefully to match document titles/numbers/dates vs the ToC 23

24. Document identification and version control (2) If you must use a file system: Give read/write access only to those who need it most –Read access only for others Maintain a “read only” area for final, approved versions Agree and enforce rules for file naming/version control –Set up a tracking spreadsheet or similar system to ensure traceability of files –Maintain an up-to-date ToC that includes full titles and dates for each document Use dates or version numbers to identify files –Avoid the use of “final” in file names 24

25. Document identification and version control (3) If you must use a file system: Avoid cryptic file names Be aware that the risk of misidentification is heightened in certain circumstances: –Reports with very similar titles or study numbers can be mixed up –The same applies with literature references Smith & Jones 1990a, Smith & Jones 1990b Check documents in your submission for correct identity –Check title, author and date versus the ToC 25

26. Granularity Best practice suggestions: Make an early decision on granularity –ICH M4 allows a degree of choice between a coarser or finer granularity Choose a fine granularity for sections that may change often in future e.g. Module 2.3 and Module 3 subsections –Life cycle management only allows whole documents to be replaced, not individual pages Generate your documents at the correct granularity –Splitting or combining is time consuming and error prone, and will affect intra-document hyperlinks 26

27. Document quality Generate PDFs directly from the source files e.g. MS Word etc –avoid scanning where possible Generate PDFs to comply with recommended technical specifications for eCTD –PDF version 1.4, fonts embedded etc Make authors responsible for PDF generation, or use a validated PDF rendering engine Use Word templates set up with styles, auto captioning and electronic cross-referencing –Promotes consistent formatting –Automates creation of bookmarks and hyperlinks when the Word documents are rendered to PDF Check scanned legacy documents for completeness and legibility 27

28. Hyperlinking and bookmarking Recommendation –Bookmark headings, tables and figures –In general, hyperlink cross-references to anything not on the same page as the cross- reference however, avoid inter-document hyperlinking in Module 2.3/3 since it adds little value and is degraded during life cycle management –Use Word templates with styles, electronic captions and electronic cross-referencing Automatic creation of bookmarks and hyperlinks when rendered to PDF 28

29. Setting eCTD attributes Attributes differentiate Module 3 sections where multiplicity is allowed –2.3.S and 3.2.S “substance”, “manufacturer” –2.3.P and 3.2.P “product-name”, “dosageform”, “manufacturer” –3.2.P.4 “excipient” –3.2.A “manufacturer”, “substance”, “dosageform”, “product-name” There is no “life cycle management” for attributes –what is done now is done forever! –attributes for subsequent sequences must be consistent with previous sequences 29

30. Part 3: Particular challenges for CMC specialists 30

31. Challenges Managing content –ensuring traceability of summary information to original source data –managing documents that are used in multiple eCTDs the same product in different territories different variants of the same product different products altogether –managing versioning situations where different versions of a document have been submitted / approved in different territories –managing approval status information Making sound decisions regarding granularity Making sound decisions on attribute setting Training users –to use templates appropriately to prepare consistent documents that are submission-ready –to understand granularity –to understand attributes and their usage –to understand life cycle management 31

32. Questions? martin.moxham@i-regulatory.com 32