GlaxoSmithKline Biologicals submitted the first worksharing variation in Europe to manage changes for 21 products using a single submission. This allowed them to use a single application form, cover letter, and data package rather than submitting variations for each product individually. However, managing worksharing submissions required more coordination between GSK and regulatory authorities. While it saved resources for GSK to prepare a single dossier, it did not necessarily reduce authorities' workload as they still had to assess each product. Communication with local operating companies in other countries was also important to ensure worksharing was implemented correctly.

1. Managing and Publishing Electronic Submissions Following the New Variations Regulation Alain Seront GlaxoSmithKline Biologicals 28 – 29 September 2010 | Munich, Germany

2. GlaxoSmithKline Biologicals Over 30 marketed vaccines available worldwide 11.000 employees worldwide / 7000 in Belgium Headquarter in Belgium Manager of the Document Management and Publishing Team at GSK Bio 10 years in Pharma Regulatory operations Publishing e-submissions (project management) alain.seront@gskbio.com

3. Menu EMEA/H/xxxx/WS/001 Practical issues… Practical solutions Dossier life-cycle Document life-cycle Preparation and compilation Submission Procedure Benefits and Limitations Save Resources? Timelines Communication with affiliates

4. EMEA/H/xxxx/WS/001

5. EMEA/H/xxxx/WS/001 First worksharing submitted in Europe Type II Variation Concerns an existing building re-furbished multi-products facility Use for formulation activities 21 products

6. EMEA/H/xxxx/WS/001 Same changes applies to all products Single data package 1 single Cover Letter for CP / MRP / (National) 1 single Application Form for CP / MRP 1 single data package for CP /MRP / (National) Impacted modules: 1, 2 & 3 No need for assessment of product specific impact Marketing Authorization Holders GSK Bio for CP products GSK Local Operating Companies for some MRP products WORKSHARING

7. EMEA/H/xxxx/WS/001 Reference authority MRP chosen by CMDh based on proposal by the applicant (one of the Member States concerned) CP (+ MRP) EMA For this Worksharing

8. EMEA/H/xxxx/WS/001 Reference authority (EMA) Assess the variation Other concerned authorities share the assessment report from the Reference Authority CMDh is expecting that the National Procedure produce no re-assessment even if it is out of worksharing scope for the moment Was indeed the case

9. EMEA/H/xxxx/WS/001 1 Cover Letter: CP + MRP + National Clearly stating what is being submitted and in which format 2 Tables included with all impacted products

10. EMEA/H/xxxx/WS/001

11. Practical issues… practical solutions

12. Product A Product B Product D Product C Applies to EMEA/H/xxxx/WS/001 Worksharing / grouping (theory)

13. Dossier life-cycle How is a dossier managed in e-submissions? eCTD Managed at product level Cannot manage more than one MA (product) in a single eCTD sequence Tradename as root eCTD folder Associated with procedure number in CP (EMEA/H/C/721) and MRP/DCP (BE/H/215) NeeS 1 NeeS dossier per product

14. eCTD NeeS Product A EMEA/H/C/0123 Product B EMEA/H/C/0456 Product D DE/H/0215 Product C EMEA/H/C/0252 0000 0000 0000 0000 0000 0001 0001 0001 0002 0000 0002 0002 0003 0000 0003 0004 0004 0005 0006

15. Worksharing / grouping (reality) Content Same Dossier life-cycle Different

16. Product A EMEA/H/C/0123 Orvalrix orvalocetam 0004 0001 EMEA/H/xxxx/WS/001 Type II Variation Worksharing Product B EMEA/H/C/0456 Stellarax eurotriptan malleate 0006 0005 EMEA/H/xxxx/WS/001 Type II Variation Worksharing Product D DE/H/0215 Jupilrix parocetam 0000 - EMEA/H/xxxx/WS/001 Type II Variation Worksharing Product C EMEA/H/C/0252 Lefferox lefferizine 0002 0000 EMEA/H/xxxx/WS/001 Type II Variation Worksharing eCTD NeeS Applies to EMEA/H/xxxx/WS/001

17. Dossier meta-data (eCTD EU envelope) <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>

18. Worksharing / grouping (reality) Content Same Dossier life-cycle Dossier meta-data (eCTD EU envelope) Different

19. 0000 0000 M3 - Quality M3 - Quality 3.2 Body of Data 3.2 Body of Data 3.2.A Appendices 3.2.A Appendices 3.2.A.1 Facilities and Equipment 3.2.A.1 Facilities and Equipment Product Name: 50-AW-DD-TID – Form: 1 dose vial – Manufacturer: GSK Belgium Product Name: ACIH-IBV – Form: 1 dose syringe – Manufacturer: GSK Belgium Formulation Formulation Formulation Drawings Formulation Drawings Containment Containment Dossier structure

20. 0000 M3 - Quality 3.2 Body of Data 3.2.A Appendices 3.2.A.1 Facilities and Equipment Product Name: common – Form: common – Manufacturer: GSK Bio Formulation Formulation Drawings Containment Dossier structure

21. Worksharing / grouping (reality) Content Same Dossier life-cycle Dossier meta-data (eCTD EU envelope) Dossier structure (DS, DP, …) Different

22. Product A Product B Document life-cycle 0001 0005 0004 0006 1.2 Application Form Annex version 2 (licence numbers for all products) 1.2 Application Form Annex (licence numbers for all products) 1.2 Application Form Annex (licence numbers for all products) Replaces EMEA/H/xxxx/WS/001

23. Document life-cycle Product A Product B <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> <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>

24. Worksharing / grouping (reality) Content Same Dossier life-cycle Dossier meta-data (eCTD EU envelope) Dossier structure (DS, DP, …) Document life-cycle Different

25. Product A Product B Product D Product C Applies to EMEA/H/xxxx/WS/001

26. Product A Product B Product D Product C Same content Different envelopes Different life-cycles (sequences and documents) Different dossier structures EMEA/H/xxxx/WS/001 EMEA/H/xxxx/WS/001 EMEA/H/xxxx/WS/001 EMEA/H/xxxx/WS/001 Preparation and compilation

27. Preparation and compilation clone clone 0000 (NeeS) 0004 (eCTD) 0006 (eCTD) 0000 m1 m2 m3 m1 m2 m3 m1 m2 m3 m1 m2 m3 m1-toc ctd-toc m2-toc m3-toc eCTDpublishing tool eCTDpublishing tool eCTDpublishing tool compile compile compile util util util util index.xml index.xml index.xml index-md5.txt index-md5.txt index-md5.txt

28. Preparation and compilation 0004 import m1 m2 m3 eCTDpublishing tool paperpublishing tool publish compile util index.xml index-md5.txt

29. Preparation and compilation Cloning is possible because It’s a functionality of our publishing tool All documents are the same across products All documents are new (no replace or delete) Replaced or deleted documents? Build first sequence with all new documents Clone Add documents with life-cycle in all sequences Dossier structures are the same across products

30. Preparation and compilation Withdrawal of 3 products (1 CP, 2 MR) from the worksharing procedure (same for rejection) Relevant leaves should not appear in the current view (delete operation) But original Application Form and cover letter are not removed from the current view (keep the “history” of the dossier in current view) Updated Annex to the Application Form with Product and Member States details is replacing the previous one (replace operation) Submission type is supplemental-info (withdrawal is used to withdraw a license)

31. Current 0006 (WS001) m1 Application Form AF Annex (product list) m2 QOS m3 Facilities & Equipment Preparation and compilation m1 Cover Letter Cover Letter Application Form AF Annex (product list) m2 QOS m3 Facilities & Equipment

32. 0009 (Withdraw) 0006 m1 Application Form AF Annex (product list) Replaced by m2 QOS m3 Facilities & Equipment Preparation and compilation Current m1 m1 Cover Letter Cover Letter Cover Letter Application Form Cover Letter AF Annex (product list) AF Annex (product list) m2 m2 delete Deleted m3 m3 delete Deleted

33. Submission Procedure Submission to EMA and all member states at the same time Via central office for CP Via local operating companies (LOCs) for MRP All member states are receiving all products (CP + MRP) Copy of cover letter send to LOCs Not accepted by some Member States Additional cover letter in some countries (outside the sequence that was prepared)

34. Submission Procedure Submission to EMA and all member states at the same time Agencies are receiving and registering the dossier twice As part of the MRP / DCP (National Competent Authority) As Rapporteur / CHMP member New cover letter template (EMA, July 2010) for worksharing Includes a distribution list

35. Submission Procedure “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.”

36. Submission Procedure Dispatch 1 CD with all eCTDs 1 CD with all NeeS 1 agency trying to upload NeeS as eCTD Rejected EMA requesting 1 CD per product Contradict the eCTD Variations Q&A document from CMDh and EMA

37. Submission Procedure Tracking number According to eCTD Variations Q&A document « Tracking number = the next procedure number for this product, with the worksharing number included »

38. Submission Procedure EMEA/H/C/000123/WS005/065 EMEA/H/C/000456/WS005/014

39. Submission Procedure GSK Bio Increment the variation number to one for every product EMA Did not increment Discrepancy at the next variation Submit twice with the same variation number (twice for us, once for EMA)

40. Benefits and limitations

41. Benefits and Limitations EMEA/H/xxxx/WS/001 Submitted early February 2010 First worksharing prepared by GSK Bio, and first submitted at EMA We had to learn a lot, our local operating companies had to learn a lot, and the authorities as well

42. Benefits and Limitations Save resources? Authors and dossiers managers (Applicant): yes 1 data package = 1 Application Form, 1 Cover Letter and 1 set of supportive data instead of multiple (in our case: 21) 1 dossier to manage with authorities, one common assessment Probably assigned to some specific products Worksharing = cross-products More communication & coordination is needed

43. Benefits and Limitations Save resources? Publishing (Applicant) Yes if cloning is possible, no if sequences must be created individually 1 QC (same content) + QC on the envelopes

44. Benefits and Limitations Worksharing timelines (for our dossier) CP: same as normal procedure MRP: same a normal procedure No priority for some products They are all approved at the same time If one product requires special consideration (e.g. supply critical), need to be withdraw from worksharing Follow the longest procedure timelines (if grouping variations of different types)

45. Benefits and Limitations Worksharing timelines Variation can be implemented 30 days after receiving letter with positive opinion No local approval is expected for MRP products by National Competent Authorities Benefit from supply point of view We can implement all changes in one step for all CP and MRP products within the worksharing Could be an issue in some countries e.g. Italy: all variations for vaccines must be officialyauthorised Communication from Central Office to Affiliates, then from Affiliates to National Competent Authorities

46. Benefits and Limitations Communication with Affiliates (LOCs) Standard submission (i.e. no worksharing or grouping) Mutual Recognition Procedure + Mod. 1 Modules 2 to 5 Modules 1 to 5 GSK central office Prepares common Modules 2 to 5 GSK local office Add local Module 1 Send dossier to NCA National Competent Authority 1 2 3

47. Benefits and Limitations Communication with LOCs Worksharing Mutual Recognition Procedure Modules 1 to 5 Modules 1 to 5 GSK central office Prepares common Modules 1 to 5 GSK local office Send dossier to NCA National Competent Authority 1 2

48. Benefits and Limitations Communication with Affiliates Make sure they send the sequence as provided to them (no additional documents within the sequence) Ensure that national authorities have no additional requirements (e.g. original Application Form, Cover Letter, …) Keep them updated on progress of the dossier at EMA 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)

49. Benefits and Limitations Communication with Affiliates Make sure the dossier is not send twice to the same recipient Rapporteur CHMP National Competent Authority GSK central office Prepares common Modules 1 to 5 GSK local office Send dossier to local NCA

50. Final words A new updated version of the « eCTD variations Q&A document, CMDh and EMA » would be useful Will the next major version of eCTD, aka RPS, provide a better way to handle worksharing and grouping? Use of single instance of documentation across multiple products / MAs?

51. Thanks you to all of you who are still here to read this!

53. References eCTD Variations Q&A document, CMDh and EMA, January 2010 Q/A-List for the Submission of Variations According to Commission Regulation (EC) 1234/2008, CMDh/132/2009/Rev5, June 2010 EU Module 1.4 Specification, EMA, August 2009 CMDh Best Practice Guides for the Submission and Processing of Variations in the Mutual Recognition Procedure, CMDh/094/2003/Rev8, May 2010 European Medicines Agency / CMDh explanatory notes on Variation Application Form, CMDh/133/2010, January 2010 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 Publishing Electronic Submissions using the new Variations Guidelines, Laura Barrett, GSK, presented at the « Filing Variations 2010 » conference, June 2010

54. Worksharing: process and timeline for CP products 2 weeks before EMA deadline Submit to all CMS, pay fees Submission application Validation & WS started Agreed letter from EMA Letter of intent Dossier preparation 1-2m 2-3 weeks At least 3 m, better 4-6m 3m (no Q&A) update AR CHMP review Positive Opinion Approval letter Primary AR commitment 2-3 weeks Q&A submission CHMP/CMDh comment CHMP/CMDh review 4 weeks 4 weeks 1-2 days No clock-stop 9 weeks Positive Opinion Approval letter 44days Final Commission Decision 9 weeks 5.5 m-6.5m for Final CD (labelling change) 4m(no Clock stop) 5m (1m clock stop)

55. Worksharing: process and timeline for MRP and National procedure products MRP products Positive Opinion Approvals for MR Maybe longer than 1 m +1m National Procedure Products Positive Opinion Approvals for National Procedure product Recognition EMA PO +3-6 m

56. Submission Type, Mode & Numbers (CP) To be provided by EMA

57. Submission Type, Mode & Numbers (MRP) Submission nunber to be provided by RMS Product numberVirtual number – This number should be stored by MAH but not mentioned in application form or Cover letter