1. The European Agency for the Evaluation of Medicinal Products 1 FFUL LisbonHilde Boone - EMEA 29 May 2003 EU Variation Regulations (541/95 and 542/95) Final Proposals Evaluation and Regulation of Medicines & Health Products

2. The European Agency for the Evaluation of Medicinal Products 2 End of 2000: NL proposal agreed at Pharmaceutical Committee Commission NTA Proposals for Revision of Variation Regulations Why: Reduce workload of Competent Authorities (& industry) Simplify and improve procedures Suitable for enlargement Review Initiative

3. The European Agency for the Evaluation of Medicinal Products 3 Initial NTA Proposals 2 Variation Categories: No Assessment Type 0 notification validity check implementation (‘tell and do’) Assessment as in current Type II Reclassify Type I variations over both categories + no longer ‘Type I following Type II procedure’

4. The European Agency for the Evaluation of Medicinal Products 4 Initial NTA Proposals December 2000 First proposal drawn up for Type 0 list For chemicals/small molecules only (biologicals to be added at a later stage) Discussed at NTA meetings Comments from QWP Need to maintain Type I variations ! = 3 categories?

5. The European Agency for the Evaluation of Medicinal Products 5 Limitations: Terminology used in Dir 2001/83/EC and in Fee Regulation (Centralised Procedure) Only “Minor” and “Major” Only “Type I” and “Type II” ?? 3 categories ?? Final NTA Proposals

6. The European Agency for the Evaluation of Medicinal Products 6 Final NTA Proposals 3 Variation Categories: No Assessment Type IA notification validity check implementation (‘tell and do’) Assessment short assessment Type IB ( as in current Type I ) assessmentType II

7. The European Agency for the Evaluation of Medicinal Products 7 l MINOR VARIATIONS - Type IA - Well-defined changes: * exhaustive list * strict conditions * required documentation ---> Guideline (statements rather than data) - Notification to authorities - No assessment; no request for addit.info/clarification - Acknowledgement of validity within 14 days - Immediate implementation Minor Variations

8. The European Agency for the Evaluation of Medicinal Products 8 Minor Variations Examples Type IA: Change in name of MAH, manufacturer New secondary packaging site Tightening of specification limits Submission of new CEP from approved manuf. Deletion of manufacturing site

9. The European Agency for the Evaluation of Medicinal Products 9 Minor Variations l MINOR VARIATIONS - Type IB - Well-defined changes: * exhaustive list * strict conditions * required documentation ---> Guideline (statements and data) - Notification to authorities - Acknowledgement of start of procedure - Short assessment; within 30 days: no comments -> implement if comments -> extend by 30 days - (EMEA) positive or negative ‘Notification’

10. The European Agency for the Evaluation of Medicinal Products 10 Minor Variations Examples Type IB: Change in shelf-life Addition of test procedure ( not biologicals ) New active substance manufacturer ( not biologicals ) Change in name of product Change in primary packaging material ( not biologicals ) Minor change in manufact. process ( not biologicals )

11. The European Agency for the Evaluation of Medicinal Products 11 Annex I 48 Variation entries*, covering 51 Type IA changes 61 Type IB changes * based on list April 03

12. The European Agency for the Evaluation of Medicinal Products 12

13. The European Agency for the Evaluation of Medicinal Products 13 Major Variations l MAJOR VARIATIONS - Type II - Application to authorities - Acknowledgement of start of procedure - Assessment  60 Days TT (+ clock-stop + ext.) or shorter – urgent changes (safety) 90 Days – indications Centralised Procedure: CPMP opinion + Decision-making process without Standing Committee consultation !

14. The European Agency for the Evaluation of Medicinal Products 14 Extensions l EXTENSIONS - Annex II Full assessment required (up to 210 days) ---> Modification or extension of the MA Examples: New Strength New Route of Administration Certain changes to Active Substance All changes to / new indications  Type II

15. The European Agency for the Evaluation of Medicinal Products 15 Final NTA Proposals

16. The European Agency for the Evaluation of Medicinal Products 16 Other Proposals Urgent Safety Restrictions (USR): Interim change to the product information concerning particularly … the indications, posology, contra- indications, warnings, target species and withdrawal period due to new information having a bearing on the safe use of the medicinal product The USR shall be implemented within a defined timeframe, as agreed with the Agency The corresponding variation application reflecting the USR shall be submitted immediately and no later than 15 days after the initiation of the USR

17. The European Agency for the Evaluation of Medicinal Products 17 Other Proposals l Safety Type II Variations and USRs: to be implemented within a defined timeframe as agreed with EC/EMEA. l Type II: introduction of clock-stop (instead of extensions) l Regulation will also apply to VAMF/PMF variations l Specific provisions in CP for Human influenza vaccines (based on current practice in MR procedure ) l Update of Commission Decision Annexes after Type IA and Type IB: every 6 months l Possibility for consequential & parallel variations l Harmonised numbering system for MR and centralised variations

18. The European Agency for the Evaluation of Medicinal Products 18 Submit variation to all RMS + CMSs MAH to allocate procedure number in advance Type IA Variations: Validity check : -> only done by the RMS -> no approval by the CMS Type IB Variations: automatic validation and start by the RMS evaluation and notification only by the RMS MRP-specific issues

19. The European Agency for the Evaluation of Medicinal Products 19 no approval of the variation by the CMS is necessary “ …. variation shall be deemed to have been accepted by all national competent authorities of the MSs…” “….RMS shall inform the other national competent authorities of the MSs concerned and the MAH….” holder But, “....each CMS shall, where necessary, amend the MA...“ MRP-specific issues

20. The European Agency for the Evaluation of Medicinal Products 20 Exception: The RMS will involve the CMS for change in the name of the medicinal product (Variation No 2 of Annex I) change in pack size (Variation No 41a2 and No 41b of Annex I) => CMS to forward comments to RMS by Day-20 Right of the MAH and CMS for Arbitration within 10 days in case of negative outcome MRP-specific issues

21. The European Agency for the Evaluation of Medicinal Products 21 Type II Variations: Automatic validation procedure by RMS CMSs to comment to RMS Possibility for break-out meetings RMS is closing the procedure If the MA is not affected  no formal follow-up by CMS If the MA is affected  CMS to update national MA within 30 days following receipt of translations “....Each CMS shall, where necessary, amend the MA...“ Arbitration by CMS in all cases possible, or by MAH in case of negative outcome MRP-specific issues

22. The European Agency for the Evaluation of Medicinal Products 22 MRFG Best Practice Guide on Variations (under development) How to assign the MR-Variation Number for a variation application (guidance to MAH) Procedure for Type IA Variation Procedure for Type IB Variation Procedures for Type II Variations with timetables for- safety changes - ‚normal‘ variations - indications MRP-specific issues

23. The European Agency for the Evaluation of Medicinal Products 23 WP / Industry Consultation QWP, BWP – IWP, HMPWP: Comments on draft lists of Type IA and Type IB QWP involved at early stage PhVig WP + CxMP: Consulted on the new Regulation concepts and indication proposals + safety-specific variations Industry (Feb 02 + Oct 02): Consulted on the new Regulation concepts and draft Type IA & IB lists (no biotech) + Joint meeting NTA/WPs/Industry November 2002

24. The European Agency for the Evaluation of Medicinal Products 24 Next Steps - Finalisation Agreement at Standing Committee : 3 April 03 Publication in Official Journal: June 03 Finalisation ofApplication form & Guideline : NTA June 03 Implementation: October 03

25. The European Agency for the Evaluation of Medicinal Products 25 Implementation by EMEA / CPMP Variation Regulation Implementation Team (VRIT) Representatives of Human Units, Inspections, Directorate Different working groups: USR, Type I, Type II, Extensions, Mock-up & specimens, Fees, Translations, CD Annexes Practical proposals, handling of procedural issues Internal and external guidance documents

26. The European Agency for the Evaluation of Medicinal Products 26 Review process more difficult than initially expected Introduction of Type IA (no assessment) -> re-classification of current Type I Addition of new Type IA/IB changes (previous Type II) i.e. not currently listed as Type I Clear, detailed, unambiguous conditions and documentation requirements, agreed with assessors CONCLUSIONS easier to prepare notifications more harmonisation, less interpretation smoother validation faster approval and implementation reduction of assessors’ and MSs workload allow better industry planning

27. The European Agency for the Evaluation of Medicinal Products 27 New /changes to indications: all Type II Accelerated Type II procedure & implementation of safety-related variations Implementation agreements for safety variations Clock-stops in Type II (benchmarking, statistics ….) Simplified CP Decision-Making for Type II Opportunity to introduce process simplification in CP e.g. Translation, mock-up requirements MRP: increased role of RMS  Certain changes can be implemented at same time in all MSs CONCLUSIONS Next Steps: Prepare for implementation Monitor performance of new Regulations