1. Swissmedic Swiss Agency for Therapeutic Products Hallerstrasse 7 CH-3000 Bern www.swissmedic.ch Workshop 1 – Case Study 2nd Follow-up Information Meeting with Workshops – Step 3 Dr. Claudia Zerobin Kleist, Swissmedic Dr. Andreas Uttenweiler, Novartis 16th March 2011

2. 2 Overview 1.Introduction 2.Pre-Submission 3.Validation 3.1 Technical Validation 3.2 Content Validation 4.Review incl. LoQ and Pre-decision 5.Labelling and Decree

3. 33 Introduction Goal of the workshop  Avoid common pitfalls in preparing and submitting eCTDs and allow a smooth review process Focus on  interaction between applicant and Swissmedic during the Marketing Authorisation Process  learn how Swissmedic handles eCTD submissions  Mutual understanding and learning

4. 4 eCTD application  See Flow-chart

5. 5 Overview 1.Introduction 2.Pre-Submission 3.Validation 3.1 Technical Validation 3.2 Content Validation 4.Review incl. LoQ and Pre-decision 5.Labelling and Decree

6. 66 Pre-submission (I) Pro’s and con’s of eCTD submission or what do I have to consider when I want to switch to eCTD?  What does the audience think?  3 groups: General Manager, Regulatory Affairs Manager, Health Authority  Discuss with your colleagues (5 min.)  Write your thoughts on cards  Put the cards on the board Results see separate document

7. 7 Pre-submission (II) Getting ready for eCTD means Implications on organization and processes  Different handling of documents  Modified role of regulatory affairs department, new tasks for authors of regulatory documents (doc format, templates, granularity, blue font for hyperlinks etc.) as well as responsible persons of other groups  Changes concerning information exchange (eMail, teleconference, F2F meetings) between headquarters and affiliates (e.g. tracking tools for documents/ operators, document management system, timelines)

8. 8 Pre-submission (III) Implications on information technology (IT) tools  There is a large choice of tools available:  From complex systems with integrated document management systems stored on a central server…  … to isolated systems installed on a PC, using a shared drive

9. 9 Pre-submission (IV) Implications on change management/training  Let people participate at the solution  Involve the relevant stakeholders into the development of the solution  Role-oriented trainings (end-user, administrators) Coordination of activities  Headquarter/affiliate  Company/service provider  DRA Manager/publisher/others  Different regions/time zones

10. 10 Pre-submission (V) Questions to be clarified  What are the regulatory requirements the applicant has to follow?  Website Swissmedic: http://www.swissmedic.ch/zulassungen/00933/00934 /index.html?lang=de http://www.swissmedic.ch/zulassungen/00933/00934 /index.html?lang=de

11. 11 Pre-submission (VI) Which documents (requirements) do exist on Swissmedic’s website and what do they describe?

12. 12 Pre-submission (VII) Requirements for industry posted on Swissmedic’s website: eCTD Specification Swiss Module 1 Specification, v1.1 Overview (Website eSubmissions): http://www.swissmedic.ch/zulassungen/00933/00934/index.html?lang=en) http://www.swissmedic.ch/zulassungen/00933/00934/index.html?lang=en FAQ Business-Process Guidance for Industry, v1.2 Questions & Answers, v1.3 Swiss Validation Criteria, v1.1 Sample eCTD-Files XML-Backbone M1 Technical descriptions Swiss Module 1 (DTD, Stylesheet, Screenshots etc. ) Track changes versions highlight changes to previous version

13. 13 Pre-submission (VIII) Technical requirements  Choosing a tool  Evaluate pro’s and con’s of tools  Evaluate maturity of tools  Requirements of Swissmedic  Validation criteria and validation tools  Interpretation of criteria  FO technical validation  Basic understanding of validation criteria needed

14. 14 Pre-submission (IX) Crucial things to think of (headquarters, affiliates, external partners) – 1/2  Document granularity/templates/version management/QC (reuse documents for paper output/other countries both internally and externally, facilitate life cycle management)  Technical writing conventions (e.g. hyperlinks/end- /footnotes both within and between documents)  IT/process (archiving, avoid problems due to password protection/macros, enable printing)

15. 15 Pre-submission (X) Crucial things to think of (headquarters, affiliates, external partners) – 2/2  Roles (authoring, QC, approval, publishing, handling)  regulatory aspects (file size ＜ 100 MB, “.pdf” version 1.4, working documents as “.doc”, hyperlinking of ch- prof, eCTD specifications etc.)

16. 16 Pre-submission (XI) To ensure technical correctness: What can I do?

17. 17 Pre-submission (XII) Technical correctness is a pre-requisite for processing into review  Follow Swiss Module 1 Specification and Swiss Validation Criteria  Check the submission before you send it  Ensure technical correctness:  Test submission  Free-of-charge-validator(s)  Manual check (e. g. envelope)  Quality check (also after CD/DVD burning)  Pre-submission meetings for purely technical reasons are not possible, but may be part of such a meeting (see VV pre-submission meetings)

18. 18 Pre-submission (XIII) Timing/Planning  Crucial for eCTD submissions  Coordination with partners (outsourcing)  No last minute changes of documents possible without delay in submission

19. 19 Pre-submission (XIV) Filing  Via CD or DVD  Do not split submission over more than 1 CD/DVD  If not possible: do not split the Modules  No password protection  No zipped files  No gateway available  In case of questions: Single point of contact: esubmission@swissmedic.ch esubmission@swissmedic.ch

20. 20 Overview 1.Introduction 2.Pre-Submission 3.Validation 3.1 Technical Validation 3.2 Content Validation 4.Review incl. LoQ and Pre-decision 5.Labelling and Decree

21. Validation (I) Today‘s situation  Validation at Swissmedic is done in 2 steps:  Technical validation  Content validation  Applicants gets 2 feedbacks  Feedback on technical validation at day 10  Feedback on content validation at day 30 21

22. Validation (II) Process in re-evaluation  Pro‘s and con‘s  Combined feedback (technical + content) at day 30  Feedback on errors severity A at day 5; feedback on errors severity B/C just as content at day 30  Other possibilities? 22

23. 23 Overview 1.Introduction 2.Pre-Submission 3.Validation 3.1 Technical Validation 3.2 Content Validation 4.Review incl. LoQ and Pre-decision 5.Labelling and Decree

24. Technical Validation (I) Error classification  Severity A  submission is always rejected (Replacement submission requested)  Severity B  submission is accepted as a rule, maybe a correction with the next planned submission is requested  Severity C  Maybe suggestions for future improvement 24

25. Technical Validation (II) Swissmedic’s reasons for the technical validation of eCTD  Legal requirements: integrity of the submission (checksum)  Ensure efficient review: navigation (ease of access of information), ensure correct lifecycle management  Long term preservation: Requirement for easier technical handling (uniform file formats) 25

26. 26 Technical Validation (III) Frequent technical errors  Use of wrong DTD: since January 1, 2011 only DTD 1.1 is accepted  No Form Technical Validation submitted  no technical error in the strict sense, but technical check cannot start

27. 27 Examples of frequent technical errors with severity A (I)  A4 (DTD - checksum): Additional files in DTD-Folder (additional inserted regional dtd‘s – e.g. stf.dtd)  Mostly tool specific error Example:Validation Report:

28. 28 Examples of frequent technical errors with severity A (II)  A7 File Reference: There are no unreferenced files in the root folder, M1, M2, M3, M4 & M5 folders (including subfolders but excluding ‘util’ subfolders), the index- md5.txt and index.xml Example: Validation Report:

29. 29 Examples of frequent technical errors with severity A (III)  A20 (Sequence number has not already been used) * this criteria can only be validated in the life cycle (not part of a standalone validation):  Replacement = same sequence number  Correction in subsequent sequence = new sequence number Import Report:

30. 30 Examples of frequent technical errors with severity B (I)  B2 (CH M1 file name convention is followed e.g. FIXED-VAR.EXT, CC-FIXED-VAR.EXT, CH-FIXED- VAR.EXT): Use hyphens carfully! The var-part should not contain any hyphens: e.g.  WRONG: ch-cover-swiss-pill.pdf  CORRECT:ch-cover-swisspill.pdf Example: Validation Report:

31. 31 Examples of frequent technical errors with severity B (II)  B6 (broken links): Especially critical in Modules 1 and 2 and TOCs  Broken hyperlinks as well as the total number of hyperlinks is part of the technical validation Validation Report:

32. 32 Examples of frequent technical errors with severity B (III)  B9 (The life cycle operator “append”, “replace” or “delete” references to a valid document in previous submission)  The history of documents has to stay visible Example: Validation Report:

33. 33 Examples of frequent technical errors with severity B (IV)  B13 (checksum for every referenced file)  must be corrected with the following submission (=content validation) or may lead to a reject. The integrity of the files is not guaranteed. Validation Report:

34. 34 Examples of frequent technical errors with severity C (I)  C4 (The envelope-referenced sequence entry is valid): Baseline Submissions has no related eCTD sequence (they represent a regulatory starting point!) Example:Validation Report:

35. 35 Examples received by applicants (I) Correct description of submission with next regular submission No placeholder documents No placeholder documents. Regulatory requirements define technical pre-requisites

36. 36 Examples received by applicants (II) No external hyperlinks (can be removed from website e. g.). If needed, put pdf of the site as refernce document into the submission Labelling of submission media is important

37. 37 Val. Criteria v1.1: error severity B Document Lifecycle Examples received by applicants (III) Error severity C, but adherence is recommended

38. 38 Examples received by applicants (IV) Country code as frequent error Broken links may pass technical validation, but not content validation Violation of naming convention. Naming of leaf titles is important, but no rules available

39. 39 Examples received by applicants (V) Related eCTD Sequence Handling of dosage forms

40. 40 Form Technical Validation (I) The form technical validation has to be submitted as paper copy only (1-fold) with every submission. A copy is sent back to the applicant with Swissmedic‘s comments and decision.

41. 41 Form Technical Validation (II) FO Technical Validation (Swiss-specific). You can explain errors to Swissmedic  benefit for applicant, enhances communication  Available (only) in English  Needs to be provided with every submission  In case of errors severity A: do not submit or contact Swissmedic (esubmission@swissmedic.ch)  Make use of test submission

42. 42 Overview 1.Introduction 2.Pre-Submission 3.Validation 3.1 Technical Validation 3.2 Content Validation 4.Review incl. LoQ and Pre-decision 5.Labelling and Decree

43. 43 Content Validation  Form content validation for eCTD to be submitted (mandatory for new applications and major variations, for other application types under discussion)  Binding declaration of applicant on the submission  Technical and content validation may overlap (f. ex. envelope, Hyperlinks, Life Cycle)  Consultation between departments needed (bilateral or in the eCTD core team)

44.  Temporary (6 month)  Discuss cases (daily business)  Develop (internal) standards  Spread knowledge within the organisation  Collect data (e. g. time needed for certain activities, e. g. upload of a submission, decision on the outcome of a validation report)  Evaluate and propose improvement of processes (efficiency) eCTD Core Team

45. 45 Frequent content errors  Envelope Related sequence Dosage form  Module 1  Arranging of dosage forms  Document operators  Missing printout of md5 checksum  Checksum as paper output not dated/signed  eCTD and accompanying paper documents do not match Module 1)

46. Envelope (I)

47. Envelope (II) 47 Application Number Application Type Dosage Form MA Number Related eCTD Seq. eCTD Sequence

48. Envelope (III)  Application number (Gesuchs-ID): Has to be filled in as soon as communicated by Swissmedic  Advice if wrong or missing (adapt with next planned eCTD Sequence)  Application type (Gesuchs-Typ): Choose application type according to Swiss Module 1 Specification, app. 2  Advice if wrong or missing. More than 1 application type possible. 48 repeatable

49. Envelope (IV)  Marketing Authorisation Number: Has to be filled in as soon as communicated by Swissmedic  Advice if wrong or missing  Galenic form: Name of the dosage form in English and one national language (de,f,it), EU standard terms preferred  Advice, if e. g. spelling error, wrong designation or missing translation into national language 49

50. Envelope (V) 50 wrong correct Practical examples

51. Envelope (VI)  Related eCTD Sequence: The related eCTD- sequence-number describes the relationship of additional information to the original submission or subsequent submissions. It is always the first eCTD sequence of a regulatory activity  advice, if wrong or missing number 51

52. 52 Envelope (VII)  May be repeated, f. ex: 0003 and 0004 (0003 = new indication, 0004 = new dosage strength related to new indication  put both  None in case of no related sequence, f. ex. 0000 never has a related sequence (start of regualtory activity)

53. Envelope: Example (I) Related eCTD Sequences 53

54. Envelope: Example (II) Related eCTD Sequence 54

55. 55 Envelope: Example (III) Related Seq. 0000 Not related Seq. Swisspill, swisscompany, 65824

56. Dosage Forms in Module 1 are handled in a “Swiss-specific” way  Several dosage forms can be included into 1 eCTD  Swissmedic’s handling of dosage forms:  1 dossier per dosage form  1 authorisation number per dosage form Galenic Form (I) 56

57. galenic forms common Galenic Form (II) Swiss Module 1 57

58. Galenic Form (III) EnvelopeModule 1 58

59. Galenic Form (IV) 59

60. Galenische Form (V) 60 Galenic Form: Solution for Injection

61. 61 Examples received by applicants (I) FO content validation is checked during content validation Electronic and paper do not match Product information text in M1 must be hyperlinked to other Modules 5-fold

62. 62 Examples received by applicants (II) Related eCTD sequence Hyperlinks Bookmarks

63. 63 Overview 1.Introduction 2.Pre-Submission 3.Validation 3.1 Technical Validation 3.2 Content Validation 4.Review incl. LoQ and Pre-decision 5.Labelling and Decree

64. 64 Review incl. LoQ and Pre-decision (I)  Responses to questions: same rules apply as for new submissions  Correct lifecycle is important  see workshop 3  Submission has to be looked at in the context of the previous submissions (more complex)  Reviewers guide may help  Related Sequence is important  See previous slides

65. 65 Review incl. LoQ and Pre-decision (II)  Feedback to submission with letter containing list of questions  applicant to check and implement for further submissions  First comments with FO technical validation a/o letter content validation  Forwarding of documents vs sending a link  easier access to document

66. 66 Review incl. LoQ and Pre-decision (III)  What eCTD cannot achieve  Timelines remain unchanged  Communication Swissmedic  applicant still in paper  not part of the lifecycle (one way communication)  Main differences to EU: paper copies (signed), 5 copies of product info  Parallel review in different specialists departments possible  Assessment reports are shared within Swissmedic via common drives

67. 67 Document operator (I) Reviewer needs to see history wrong

68. 68 Document operator (II) correct wrong Which operators are correct, which are wrong? Leaf title should be specified further

69. 69 appendices 69 Cover letter

70. 70  Hyperlinking required:  Information for professionals  Form pharmaceutical information for parenteral preparations  Responses to questions  The information for professionals must be hyperlinked to Modules 2 - 5 (no change compared to paper)  Hyperlinking can be done either in 2 steps (from information for professionals to list of references, from there to the source) or in 1 step  If technically possible hyperlinking directly to a specific location in the document is recommended Hyperlinking from Module 1 to other modules

71. 71 No more paper piles….

72. 72 Reviewer’s access to data  The eCTD data objects are handled according to defined processes and in defined functional data management areas

73. 73 Internal handling of eCTD sequences (I) 73 Amended by CM Link provided by DBW

74. 74 Internal handling of eCTD sequences (II) 74 Links provided by DBW

75. 75 Ex.: Information for professionals (I) Questions Module 1.3.1 (information for professionals):  How would you submit first a change of product information and then (while the var-pi is still pending) a new indication?  Which operators would you place for which document?  How would you proceed when the var-pi is approved?  Group discussion 10 min.  Presentation of proposed solution

76. 76 Ex.: Information for professionals (II) Possible solution Submission var-pi 1.3.1 Information for professionals ch-prof-swisspill-approved ch-prof-swisspill-varpi-proposed Submission na-ie 1.3.1 Information for professionals ch-prof-swisspill-approved ch-prof-swisspill-varpiproposed ch-prof-swisspill-naieproposed

77. 77 Ex.: Information for professionals (III) 1.3.1 Information for professionals ch-prof-swisspill-approved ch-prof-swisspill-varpiproposed ch-prof-swisspill-naieproposed replace

78. 78 Overview 1.Introduction 2.Pre-Submission 3.Validation 3.1 Technical Validation 3.2 Content Validation 4.Review incl. LoQ and Pre-decision 5.Labelling and Decree

79. 79 Labelling and Decree (I)  See guideline on deadlines for applications (“Richtlinie Fristen Zulassungsgesuche”)

80. 80 Labelling and Decree (II)  Do not submit documents that have not been requested by Swissmedic at this point in time  More time needed to prepare the eCTD submission in comparison to a paper submission  Make sure that the time needed for the building of the new sequence is accurately planned and the timeslot for publishing is available  Decree: maybe the applicant is asked to submit a consolidation sequence with final PI

81. 81 Labelling and Decree (III) Information for professionals, patient information  Need to be provided as working documents  Working documents in word format (no docx!)  Process for working with electronic copies within Swissmedic needs to be further developed  Applicant will receive print-out of the word document containing corrections/comments  No electronic transmission of product information texts possible today

82. 82 Any further questions? eCTD Seq. 0001 Dr. Andreas Uttenweiler Novartis Pharma Schweiz AG andreas.uttenweiler@novartis.com Dr. Claudia Zerobin Kleist Swissmedic Claudia.zerobin@swissmedic.ch