C5 eCTD Summit: Electronic submissions and the new Variations Regulation

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Managing and Publishing Electronic Submissions Following the New Variations Regulation (Worksharing and Grouping)
C5 eCTD Summit - September 2010 - Munich, Germany

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C5 eCTD Summit: Electronic submissions and the new Variations Regulation

  1. 1. Managing and Publishing Electronic Submissions Following the New Variations Regulation<br />Alain Seront<br />GlaxoSmithKline Biologicals<br />28 – 29 September 2010 | Munich, Germany<br />
  2. 2. GlaxoSmithKline Biologicals<br />Over 30 marketed vaccines available worldwide<br />11.000 employees worldwide / 7000 in Belgium<br />Headquarter in Belgium<br />Manager of the Document Management and Publishing Team at GSK Bio<br />10 years in Pharma<br />Regulatory operations<br />Publishing<br />e-submissions (project management)<br />alain.seront@gskbio.com<br />
  3. 3. Menu<br />EMEA/H/xxxx/WS/001<br />Practical issues… Practical solutions<br />Dossier life-cycle<br />Document life-cycle<br />Preparation and compilation<br />Submission Procedure<br />Benefits and Limitations<br />Save Resources?<br />Timelines<br />Communication with affiliates<br />
  4. 4. EMEA/H/xxxx/WS/001<br />
  5. 5. EMEA/H/xxxx/WS/001<br />First worksharing submitted in Europe<br />Type II Variation<br />Concerns an existing building<br />re-furbished multi-products facility<br />Use for formulation activities<br />21 products <br />
  6. 6. EMEA/H/xxxx/WS/001<br />Same changes applies to all products<br />Single data package<br />1 single Cover Letter for CP / MRP / (National)<br />1 single Application Form for CP / MRP<br />1 single data package for CP /MRP / (National)<br />Impacted modules: 1, 2 & 3<br />No need for assessment of product specific impact<br />Marketing Authorization Holders<br />GSK Bio for CP products<br />GSK Local Operating Companies for some MRP products<br />WORKSHARING<br />
  7. 7. EMEA/H/xxxx/WS/001<br />Reference authority<br />MRP<br />chosen by CMDh based on proposal by the applicant (one of the Member States concerned)<br />CP (+ MRP)<br />EMA<br />For this Worksharing<br />
  8. 8. EMEA/H/xxxx/WS/001<br />Reference authority (EMA)<br />Assess the variation<br />Other concerned authorities share the assessment report from the Reference Authority<br />CMDh is expecting that the National Procedure produce no re-assessment even if it is out of worksharing scope for the moment<br />Was indeed the case<br />
  9. 9. EMEA/H/xxxx/WS/001<br />1 Cover Letter: CP + MRP + National<br />Clearly stating what is being submitted and in which format<br />2 Tables included with all impacted products<br />
  10. 10. EMEA/H/xxxx/WS/001<br />
  11. 11. Practical issues… practical solutions<br />
  12. 12. Product A<br />Product B<br />Product D<br />Product C<br />Applies to<br />EMEA/H/xxxx/WS/001<br />Worksharing / grouping (theory)<br />
  13. 13. Dossier life-cycle<br />How is a dossier managed in e-submissions?<br />eCTD<br />Managed at product level<br />Cannot manage more than one MA (product) in a single eCTD sequence<br />Tradename as root eCTD folder<br />Associated with procedure number in CP (EMEA/H/C/721) and MRP/DCP (BE/H/215)<br />NeeS<br />1 NeeS dossier per product<br />
  14. 14. eCTD<br />NeeS<br />Product A<br />EMEA/H/C/0123<br />Product B<br />EMEA/H/C/0456<br />Product D<br />DE/H/0215<br />Product C<br />EMEA/H/C/0252<br />0000<br />0000<br />0000<br />0000<br />0000<br />0001<br />0001<br />0001<br />0002<br />0000<br />0002<br />0002<br />0003<br />0000<br />0003<br />0004<br />0004<br />0005<br />0006<br />
  15. 15. Worksharing / grouping (reality)<br />Content<br />Same<br />Dossier life-cycle<br />Different<br />
  16. 16. Product A<br />EMEA/H/C/0123<br />Orvalrix<br />orvalocetam<br />0004<br />0001<br />EMEA/H/xxxx/WS/001<br />Type II Variation<br />Worksharing<br />Product B<br />EMEA/H/C/0456<br />Stellarax<br />eurotriptan malleate<br />0006<br />0005<br />EMEA/H/xxxx/WS/001<br />Type II Variation<br />Worksharing<br />Product D<br />DE/H/0215<br />Jupilrix<br />parocetam<br />0000<br />-<br />EMEA/H/xxxx/WS/001<br />Type II Variation<br />Worksharing<br />Product C<br />EMEA/H/C/0252<br />Lefferox<br />lefferizine<br />0002<br />0000<br />EMEA/H/xxxx/WS/001<br />Type II Variation<br />Worksharing<br />eCTD<br />NeeS<br />Applies to<br />EMEA/H/xxxx/WS/001<br />
  17. 17. Dossier meta-data (eCTD EU envelope)<br /><eu:eu-backbone …> <eu-envelope> <envelope country="emea"> <submission type="var-type2" mode="worksharing"> <number>EMEA/H/xxxx/WS/001</number> <tracking> <number>EMEA/H/C/000123/WS001/014</number> </tracking> </submission> <applicant>GlaxoSmithKline Biologicals</applicant> <agency code="EU-EMEA" /> <procedure type="centralised" /> <invented-name>Orvalrix</invented-name> <inn>orvalocetam</inn> <sequence>0004</sequence> <related-sequence>0001</related-sequence> <submission-description>Multi-product site transfers </submission- description> </envelope></eu-envelope><br />
  18. 18. Worksharing / grouping (reality)<br />Content<br />Same<br />Dossier life-cycle<br />Dossier meta-data (eCTD EU envelope)<br />Different<br />
  19. 19. 0000<br />0000<br />M3 - Quality<br />M3 - Quality<br />3.2 Body of Data<br />3.2 Body of Data<br />3.2.A Appendices<br />3.2.A Appendices<br />3.2.A.1 Facilities and Equipment<br />3.2.A.1 Facilities and Equipment<br />Product Name: 50-AW-DD-TID – Form: 1 dose vial – Manufacturer: GSK Belgium<br />Product Name: ACIH-IBV – Form: 1 dose syringe – Manufacturer: GSK Belgium<br />Formulation<br />Formulation<br />Formulation Drawings<br />Formulation Drawings<br />Containment<br />Containment<br />Dossier structure<br />
  20. 20. 0000<br />M3 - Quality<br />3.2 Body of Data<br />3.2.A Appendices<br />3.2.A.1 Facilities and Equipment<br />Product Name: common – Form: common – Manufacturer: GSK Bio<br />Formulation<br />Formulation Drawings<br />Containment<br />Dossier structure<br />
  21. 21. Worksharing / grouping (reality)<br />Content<br />Same<br />Dossier life-cycle<br />Dossier meta-data (eCTD EU envelope)<br />Dossier structure (DS, DP, …)<br />Different<br />
  22. 22. Product A<br />Product B<br />Document life-cycle<br />0001<br />0005<br />0004<br />0006<br />1.2 Application Form Annex version 2 (licence numbers for all products)<br />1.2 Application Form Annex (licence numbers for all products)<br />1.2 Application Form Annex (licence numbers for all products)<br />Replaces<br />EMEA/H/xxxx/WS/001<br />
  23. 23. Document life-cycle<br />Product A<br />Product B<br /><m1-eu> <<m1-2-form>> <specific country="emea"> <leaf operation="replace" modified-file="../../../0001/m1/eu/eu- regional.xml#i-2948-18272" xlink:href="12-form/emea/emea- form-annex.pdf" xlink:type="simple" checksum-type="md5" ID="i-3337-19776" application-version="PDF 1.4" checksum="22eb3e3f5a99a7fe45a7db577c92b192"> <title>Application Form - Annex</title> </leaf><br /> <m1-eu> <<m1-2-form>> <specific country="emea"> <leaf operation="replace" modified-file="../../../0005/m1/eu/eu- regional.xml#i-3812-14569" xlink:href="12-form/emea/emea- form-annex.pdf" xlink:type="simple" checksum-type="md5" ID="i-2587-56987" application-version="PDF 1.4" checksum="22eb3e3f5a99a7fe45a7db577c92b192"> <title>Application Form - Annex</title> </leaf><br />
  24. 24. Worksharing / grouping (reality)<br />Content<br />Same<br />Dossier life-cycle<br />Dossier meta-data (eCTD EU envelope)<br />Dossier structure (DS, DP, …)<br />Document life-cycle<br />Different<br />
  25. 25. Product A<br />Product B<br />Product D<br />Product C<br />Applies to<br />EMEA/H/xxxx/WS/001<br />
  26. 26. Product A<br />Product B<br />Product D<br />Product C<br />Same content<br />Different envelopes<br />Different life-cycles (sequences and documents)<br />Different dossier structures<br />EMEA/H/xxxx/WS/001<br />EMEA/H/xxxx/WS/001<br />EMEA/H/xxxx/WS/001<br />EMEA/H/xxxx/WS/001<br />Preparation and compilation<br />
  27. 27. Preparation and compilation<br />clone<br />clone<br />0000 (NeeS)<br />0004 (eCTD)<br />0006 (eCTD)<br />0000<br />m1<br />m2<br />m3<br />m1<br />m2<br />m3<br />m1<br />m2<br />m3<br />m1<br />m2<br />m3<br /> m1-toc<br /> ctd-toc<br /> m2-toc<br /> m3-toc<br />eCTDpublishing tool<br />eCTDpublishing tool<br />eCTDpublishing tool<br />compile<br />compile<br />compile<br />util<br />util<br />util<br />util<br />index.xml<br />index.xml<br />index.xml<br />index-md5.txt<br />index-md5.txt<br />index-md5.txt<br />
  28. 28. Preparation and compilation<br />0004<br />import<br />m1<br />m2<br />m3<br />eCTDpublishing tool<br />paperpublishing tool<br />publish<br />compile<br />util<br />index.xml<br />index-md5.txt<br />
  29. 29. Preparation and compilation<br />Cloning is possible because<br />It’s a functionality of our publishing tool<br />All documents are the same across products<br />All documents are new (no replace or delete)<br />Replaced or deleted documents?<br />Build first sequence with all new documents<br />Clone<br />Add documents with life-cycle in all sequences<br />Dossier structures are the same across products<br />
  30. 30. Preparation and compilation<br />Withdrawal of 3 products (1 CP, 2 MR) from the worksharing procedure (same for rejection)<br />Relevant leaves should not appear in the current view (delete operation)<br />But original Application Form and cover letter are not removed from the current view (keep the “history” of the dossier in current view)<br />Updated Annex to the Application Form with Product and Member States details is replacing the previous one (replace operation)<br />Submission type is supplemental-info (withdrawal is used to withdraw a license)<br />
  31. 31. Current<br />0006 (WS001)<br />m1<br />Application Form <br />AF Annex (product list)<br />m2<br />QOS<br />m3<br />Facilities & Equipment<br />Preparation and compilation<br />m1<br />Cover Letter<br />Cover Letter<br />Application Form <br />AF Annex (product list)<br />m2<br />QOS<br />m3<br />Facilities & Equipment<br />
  32. 32. 0009 (Withdraw)<br />0006<br />m1<br />Application Form <br />AF Annex (product list)<br />Replaced by<br />m2<br />QOS<br />m3<br />Facilities & Equipment<br />Preparation and compilation<br />Current<br />m1<br />m1<br />Cover Letter<br />Cover Letter<br />Cover Letter<br />Application Form<br />Cover Letter<br />AF Annex (product list)<br />AF Annex (product list)<br />m2<br />m2<br />delete<br />Deleted<br />m3<br />m3<br />delete<br />Deleted<br />
  33. 33. Submission Procedure<br />Submission to EMA and all member states at the same time<br />Via central office for CP<br />Via local operating companies (LOCs) for MRP<br />All member states are receiving all products (CP + MRP)<br />Copy of cover letter send to LOCs<br />Not accepted by some Member States<br />Additional cover letter in some countries (outside the sequence that was prepared)<br />
  34. 34. Submission Procedure<br />Submission to EMA and all member states at the same time<br />Agencies are receiving and registering the dossier twice<br />As part of the MRP / DCP (National Competent Authority)<br />As Rapporteur / CHMP member<br />New cover letter template (EMA, July 2010) for worksharing<br />Includes a distribution list<br />
  35. 35. Submission Procedure<br />“When the submission address for Rapporteur/CHMP members is identical to the submission address for the national competent authorities, no additional copies of the application should be sent separately to the Rapporteur/CHMP member concerned. However, the cover letter should be copied to the CHMP member concerned.”<br />
  36. 36. Submission Procedure<br />Dispatch<br />1 CD with all eCTDs<br />1 CD with all NeeS<br />1 agency trying to upload NeeS as eCTD<br />Rejected<br />EMA requesting 1 CD per product<br />Contradict the eCTD Variations Q&A document from CMDh and EMA<br />
  37. 37. Submission Procedure<br />Tracking number<br />According to eCTD Variations Q&A document<br />« Tracking number = the next procedure number for this product, with the worksharing number included »<br />
  38. 38. Submission Procedure<br />EMEA/H/C/000123/WS005/065<br />EMEA/H/C/000456/WS005/014<br />
  39. 39. Submission Procedure<br />GSK Bio<br />Increment the variation number to one for every product<br />EMA<br />Did not increment<br />Discrepancy at the next variation<br />Submit twice with the same variation number (twice for us, once for EMA)<br />
  40. 40. Benefits and limitations<br />
  41. 41. Benefits and Limitations<br />EMEA/H/xxxx/WS/001<br />Submitted early February 2010<br />First worksharing prepared by GSK Bio, and first submitted at EMA<br />We had to learn a lot, our local operating companies had to learn a lot, and the authorities as well<br />
  42. 42. Benefits and Limitations<br />Save resources?<br />Authors and dossiers managers (Applicant): yes<br />1 data package = 1 Application Form, 1 Cover Letter and 1 set of supportive data instead of multiple (in our case: 21)<br />1 dossier to manage with authorities, one common assessment<br />Probably assigned to some specific products<br />Worksharing = cross-products<br />More communication & coordination is needed<br />
  43. 43. Benefits and Limitations<br />Save resources?<br />Publishing (Applicant)<br />Yes if cloning is possible, no if sequences must be created individually<br />1 QC (same content) + QC on the envelopes<br />
  44. 44. Benefits and Limitations<br />Worksharing timelines (for our dossier)<br />CP: same as normal procedure<br />MRP: same a normal procedure<br />No priority for some products<br />They are all approved at the same time<br /> If one product requires special consideration (e.g. supply critical), need to be withdraw from worksharing<br />Follow the longest procedure timelines (if grouping variations of different types)<br />
  45. 45. Benefits and Limitations<br />Worksharing timelines<br />Variation can be implemented 30 days after receiving letter with positive opinion<br />No local approval is expected for MRP products by National Competent Authorities<br />Benefit from supply point of view<br />We can implement all changes in one step for all CP and MRP products within the worksharing<br />Could be an issue in some countries<br />e.g. Italy: all variations for vaccines must be officialyauthorised<br />Communication from Central Office to Affiliates, then from Affiliates to National Competent Authorities<br />
  46. 46. Benefits and Limitations<br />Communication with Affiliates (LOCs)<br />Standard submission (i.e. no worksharing or grouping)<br />Mutual Recognition Procedure<br />+ Mod. 1<br />Modules 2 to 5<br />Modules 1 to 5<br />GSK central office<br />Prepares common<br />Modules 2 to 5<br />GSK local office<br />Add local Module 1<br /> Send dossier to NCA<br />National<br />Competent Authority<br />1<br />2<br />3<br />
  47. 47. Benefits and Limitations<br />Communication with LOCs<br />Worksharing<br />Mutual Recognition Procedure<br />Modules 1 to 5<br />Modules 1 to 5<br />GSK central office<br />Prepares common<br />Modules 1 to 5<br />GSK local office<br />Send dossier to NCA <br />National<br />Competent Authority<br />1<br />2<br />
  48. 48. Benefits and Limitations<br />Communication with Affiliates<br />Make sure they send the sequence as provided to them (no additional documents within the sequence)<br />Ensure that national authorities have no additional requirements (e.g. original Application Form, Cover Letter, …)<br />Keep them updated on progress of the dossier at EMA<br />e.g. Positive opinion letter send to GSK Bio only (=contact point for the worksharing procedure) and not to other concerned Marketing Authorisation Holders (GSK LOCs in some countries)<br />
  49. 49. Benefits and Limitations<br />Communication with Affiliates<br />Make sure the dossier is not send twice to the same recipient<br />Rapporteur<br />CHMP<br />National<br />Competent Authority<br />GSK central office<br />Prepares common<br />Modules 1 to 5<br />GSK local office<br />Send dossier to local NCA <br />
  50. 50. Final words<br />A new updated version of the « eCTD variations Q&A document, CMDh and EMA » would be useful<br />Will the next major version of eCTD, aka RPS, provide a better way to handle worksharing and grouping?<br />Use of single instance of documentation across multiple products / MAs?<br />
  51. 51. Thanks you to all of you who are still here to read this!<br />
  52. 52.
  53. 53. References<br />eCTD Variations Q&A document, CMDh and EMA, January 2010<br />Q/A-List for the Submission of Variations According to Commission Regulation (EC) 1234/2008, CMDh/132/2009/Rev5, June 2010<br />EU Module 1.4 Specification, EMA, August 2009<br />CMDh Best Practice Guides for the Submission and Processing of Variations in the Mutual Recognition Procedure, CMDh/094/2003/Rev8, May 2010<br />European Medicines Agency / CMDh explanatory notes on Variation Application Form, CMDh/133/2010, January 2010<br />EMA Template Cover letter for worksharing procedures including centrally authorised products (CAPs) and MRP for the submission of variation application dossier(s) for a worksharing procedure to the European Medicines Agency and National Competent Authorities according to Article 20 of Regulation 1234/2008 http://www.ema.europa.eu/pdfs/human/regaffair/letter_worksharing_caps_mrp.doc<br />Publishing Electronic Submissions using the new Variations Guidelines, Laura Barrett, GSK, presented at the « Filing Variations 2010 » conference, June 2010<br />
  54. 54. Worksharing: process and timeline for CP products<br />2 weeks before EMA deadline<br />Submit to all CMS, pay fees<br />Submission application<br />Validation & WS started<br />Agreed letter<br /> from EMA<br />Letter <br />of intent<br />Dossier preparation<br />1-2m<br />2-3 weeks <br />At least 3 m, better 4-6m<br />3m (no Q&A)<br /> update AR<br />CHMP<br /> review<br />Positive Opinion<br />Approval letter<br />Primary AR <br />commitment<br />2-3 weeks <br />Q&A<br />submission<br /> CHMP/CMDh<br /> comment<br /> CHMP/CMDh<br /> review <br />4 weeks <br />4 weeks <br />1-2 days<br />No clock-stop<br />9 weeks <br />Positive<br />Opinion<br />Approval<br /> letter<br />44days <br />Final Commission <br />Decision<br />9 weeks <br />5.5 m-6.5m for Final CD<br />(labelling change) <br />4m(no Clock stop) <br />5m (1m clock stop)<br />
  55. 55. Worksharing: process and timeline for MRP and National procedure products <br />MRP products<br />Positive<br />Opinion<br /> Approvals<br /> for MR<br />Maybe longer than 1 m<br />+1m<br />National Procedure Products<br />Positive<br />Opinion<br />Approvals for<br />National Procedure product<br />Recognition EMA PO <br />+3-6 m<br />
  56. 56. Submission Type, Mode & Numbers (CP)<br />To be provided by EMA<br />
  57. 57. Submission Type, Mode & Numbers (MRP)<br />Submission nunber to be provided by RMS<br />Product numberVirtual number – This number should be stored by MAH but not mentioned in application form or Cover letter<br />

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