Revision of the Variations Regulation. Key Principles and Guidelines Development CONTENT

Transcription

1 DIA/EMEA/CMD(h) Conference London 26 October 2009 Revision of the Variations Regulation - Key Principles and Guidelines Development Hilde Boone EMEA 1 1 CONTENT 1. Background & revision status 2. Types of Variations / classification 3. Procedures and timeframes 4. Grouping 5. Worksharing 6. Benefits for authorities and industry 7. Guidelines preparation 8. Implementation status 2 2 1

2 1. Background & Status Commission Regulations (EC) 1084 & 1085/2003 (CP, MRP products not nationally approved) Considerable burden for industry and authorities Commission: Review project launched in 2006 Better Regulation Objectives: - Clearer, simpler, more flexible - Reduce administrative burden - Adapt to ICH concepts - Further harmonise handling of variations in EU without compromising human and animal health 3 3 Variation Regulation Review (Comitology): - New Regulation EC No 1234/2008 published on 18 Dec 08 Official Journal L 334/7 of 12/12/ Regulation will apply from 1 January 2010 Except Art 5 > from 1 January CP and MRP/DCP products only EU Harmonisation Regulation to also apply to NAPs: - Council & Parliament Co-Decision procedure - Directive 2009/53 amending Directive Dir 2001/83 (82) published on 30 June Member States to transpose by 20 January Possible Opt-Out clause for MSs, for products authorised before 1 January 1998 and only in 1 MS - Subsequent Comitology procedure to include NAPs in Regulation 4 4 2

3 Transitional Matters (Art 27): Regulations 1084/2003 & 1085/2003 shall continue to apply to valid notifications or applications for variations which are pending on 1 January 2010 Agreed EC-EMEA-CMD interpretation: Use Submission Date as cut-off point Submission < 1 Jan 2010: Reg. 1084(5)/2003 Submission 1 Jan 2010: Reg. 1234/ Types of Variations Changes not requiring any prior approval Changes requiring prior approval Design Space Minor Type IA Do and tell Minor Type IB Variations Major Type II Extension Evaluation Procedure adapted to the level of risk 6 6 3

4 Classification Rules Variation Regulation: Extensions: defined in Annex I of the Regulation (e.g. new strength) Annex II of Regulation: high-level classification of Type IA + II changes Changes which are not Type IA or II: Type IB by default, with option for - MAH to submit as Type II - Competent Authority to require Type II at validation (safeguard-clause) Commission Guideline (Art 4): Classification Guideline complements Regulation by - clarifying scope of some of the Annex II variations - providing guidance on classification of additional variations List of variations classified as Type IA, Type IA IN, Type II Variations classified as Type IB provided as examples 7 7 Art 5 Recommendations Possibility to request a Recommendation on unforseen (unclassified) variations, before submission NAP: via CMD CAP: via EMEA 45 Day procedure Recommendation sent to MAH, all MSs and EMEA Publish recommendations EMEA & CMD to ensure coherence of recommendations Basis for periodic review of guideline, and Annex II 8 8 4

5 3. Procedures & Timeframes Type IA: Do and Tell approach i.e. MAH can implement New Notify change(s) within 12 months ( Annual Report ) or, immediate notification for certain Type IA required for the continuous supervision of product = IA IN 30 days timetable to review MA to be updated within 2 (IA) or 6 months (IA IN ) Type IB: Same procedural handling as current 30 (+30+30) days timetable Implement after RMS/EMEA review, or after 30 days if no feedback MA to be updated within 6 months 9 9 Type II: Same procedural handling as current 60 days default timetable 30 days for urgent variations 90 days for changes to / new indication Referral possible to CMD ---> to CHMP Implement 30 days after RMS decision CAP: after MA update MA to be updated within 2 months or 30 days (Paed) Extension: Same procedural handling as current 210 days review timetable, as for initial MAA can be granted separate MA (some MSs) can be included in same MA as initial MA (CP, some MSs) USR: Same 24h procedural handling as current corresponding variation submitted within 15 days

6 4. Grouping of Variations General Rule = Possibility to combine different variations relating to one MA in one application Type IA: Group of different Type IAs for one MA But, also: same Type IA or group of Type IAs for different MAs of same MAH Other variations: Groups pre-defined in Annex III of Reg. Different Variations applying to one MA Handled according to highest classification (e.g. Extension with related Type II Changes to ASMF, PMF Changes to manufacturing process Changes to PhVig System) Or, other groups agreed with RMS/EMEA Recommend to consult RMS/EMEA in advance CMD + EMEA will publish examples of groups which would be acceptable Should concern consequential or related changes > meaningful to review the changes in one assessment Not All or Nothing outcome approach MAH may withdraw certain claims / requested changes from a Grouped variation application, so that a positive Opinion / Notification could be issued for the approvable changes. Or, composite Notification/Opinion which lists negative & positive parts. Same level of transparency on outcome, whether a variation is refused/withdrawn as part of a group or individually

7 5. Worksharing General Rule = Possibility to combine same variation(s) relating to more than one MA of the same MAH in one application Definition of same MAH -> EC Communication 98/C 229/03: applicants belonging to the same mother company or group of companies have to be taken as one entity. Applicants which, [.] have concluded agreements (e.g. licensees ) or which exercise concerted practices concerning the placing on the market of the relevant medicinal product in different MSs, also have to be taken as one. Application to be reviewed by a Reference Authority Reference Authority: one MS chosen by CMD considering MAH recommendation EMEA: for CAPs or for groups of MAs containing at least 1 CAP MAH 1 MAH 1 Prod. 1 IB (1) Prod. 1 II (1) Prod. 2 IB (1) Prod. 2 II (1) MAH 1 MAH 1 II (1) IB (1) Prod. 1 IB (1) Prod. 1 IA (1) IA (1) Prod. 2 IB (1) Prod. 2 II (1) IB (1) IA (1) IA (1) Extensions excluded from work-sharing

8 60+ days procedure for Type IB or Type II worksharing 30+ if urgent, 90+ for variations listed in Annex V of Reg. EMEA: Resulting in CxMP Opinion in all cases MRP Submit to Ref. auth. + all CMS CP Submit to EMEA (+ NCAs of NAPs) Ref. auth. validation EMEA validation Ref. auth. review (30/60/90 days) CxMP review (30/60/90 days) Possible request for supplementary info Possible request for supplement. info Clock-stop for MAH to provide answers Clock-stop for MAH to provide answers Extension of review period to assess answ. Extension of review period to asses Ref. auth. Opinion to MAH & CMS CxMP Opinion to MAH*+ MSs + EC CMS to approve Opinion within 30 days* within 15 days of adoption. MSs to update MA (if necessary) EC to update MA (if necessary) MSs to approve Final Opinion & update MA within 30 days (if necessary) *possibility for MS to refer to CMD * possibility MAH to request re-examin. possibility MS to trigger Art 31 referral Recommended to inform RMS/EMEA in advance CMD to decide on reference authority at the following plenary CMD; EMEA to appoint (Co-)Rapporteur CMD + EMEA will publish examples of worksharing cases Same change(s) applying to different MAs; same data set; no or limited need for any additional product-specific assessment Worksharing OK One application; but individual (e-)ctd / NEES per MA Specific assessment procedure for worksharing; similar to handling of Type II variation Opinion Variations can be implemented: - Type IB: after Ref MS/CxMP positive opinion - Type II: 30 days after Ref MS/CxMP positive opinion Referral possible to CMD --->to CHMP MA to be updated within 1 month

9 6. Benefits for Authorities & Industry Type IA do & tell : * Possibility for industry to implement minor changes when needed, without awaiting authorities approval * Authorities to use resources more efficiently Type IB by default: * Less heavy procedure for unclassified variations Grouping: * possibility to submit (MAH) and review (authorities) related changes as part of one application Worksharing: * possibility to submit and review the same variation(s) for multiple products as part of one application Implementation: * Type IA: MAH s choice * Type IB, Type II: clearer rules for implementation, not awaiting MA update in each MS Detailed classification guideline: * More flexible system (incl Art 5) + possibility for regular updates Referrals: * introduction of referral step to CMD, before referring to CHMP Regulation - Harmonisation: * Same rules will apply to the handling of variations accross procedures More responsibility to MAH (e.g. Type IA 12-month reporting) Possible inspection, non-compliance issues More options available to MAH consider pro/cons, consider impact on overall timelines.. consequences for dossier maintenance, ectd impact more need for case-by-case decisions more need for pre-submission discussions with authorities? Unclassified changes: careful consider Type IB vs Type II Risk for delay in handling of variation, risk for inconsistent approaches Need for appropriate use of Grouping & Worksharing Grouping & Worksharing: increased complexicity for procedure numbering, application form, ectd

10 7. Guidelines preparation Commission Regulation (EC) No 1234/2008 Article 4(1): Guideline on the details of the various categories of variations ( Classification Guideline ) ) Guideline on the operation of the procedures ( Procedural Guideline ) February 2009: Joint contribution for guidelines prepared by EMEA, CMD(h), CMD(v), CHMP, CVMP «EU Variations Task Force» Commission: External Consultation on draft guidelines by 18 May 2009 Review of comments, with input from Task Force Industry workshops in April (all) and July (biologicals)

11 a. Draft Classification Guideline Prepared by experts from CxMP Working Parties, CMDs and EMEA (Human+Vet, Small+Large MSs, NCE+Biol, Assessor+Regulat+Inspect) Based on Regulation Annex II - list of variations Experience with current variations guideline Comments received from industry, MSs in earlier consultations Taking into account objectives of Variation Regulation revision default Type IB classification rule need to include classification for Safety/Efficacy var. impact of (re-)classification of a change on workload Specific variations classified as Type IA, Type IA IN and Type II Variations classified as Type IB provided as examples facilitate planning, submission preparation indicate expected supportive documentation increase predictability ensure consistent validation approach avoid need for Art 5 recommendation procedures Guideline annex example - Decision tree approach x Change in test procedure for an excipient Conditions to be fulfilled Documentation to be supplied Procedu re type a) Minor changes to an approved test procedure 1, 2, 3, 4 1, 2 IA b) Deletion of a test procedure if an alternative test procedure is already authorised. c) Replacement of a biological/immunological test method or a method using a biological reagent 5 1 IA II d) Other changes to a test procedure 1, 2 IB If Type IA condition not met and If not listed as a Type II Default Type IB Unforeseen Variation Draft Variation Application Form: x Change in test procedure for an excipient Procedure type b) Deletion of a test procedure if an alternative test procedure is already authorised. IA IB

12 b. Draft Procedural Guideline Based on discussions in the CMD Variations Subgroup & EMEA VRIT Team CMD h+v Variations Subgroup Human & Vet working group Rapporteurs appointed for various topics re. new handling of variations i in MRP, e.g. Art 5 recommendations Type IA Worksharing CTS update Etc. EMEA VRIT Team Human & Vet & cross-sector working group Subgroups set-up for various topics re. new handling of variations i in CP, e.g. Art 5 recommendations Type IA Worksharing Decision-making process Etc. Meet in margins of CMDh meetings Outcome endorsed by plenary CMDh / CMDv Outcome endorsed by EMEA Task Force + CHMP / CVMP Joint CMD + EMEA discussions to ensure harmonised approach where possible and dto agree on handling of f common activities iti (e.g. Art At5, worksharing) Input to Commission Guidelines Revision of CMD Best Practice Guides & EMEA Post-Authorisation PAG Basis for Procedural Guideline Development Variation Regulation Existing NTA Chapter 5 on variations Existing CMD Best Practice Guides and EMEA Post-Authorisation Guide Suggestions & concerns expressed by industry representatives at external conferences, Interested Parties meetings or in contributions Experience Taking into account.. objectives of Variation Regulation revision impact on workload harmonised approach in MRP & CP (where feasible)

13 8. Implementation status Commission guidelines in final stages Publication of final draft EN versions November 2009 Article 5 Recommendation procedures available More detailed practical guidance will be given in CMD Best Practice Guides and EMEA Post-Authorisation Guidance, SOPs Variation Application Form to be published Nov 09 e-application Form to be developed Updated ectd Module 1 specification published Aug 09 Additional practical ectd guidance to be issued Nov 09 Implementation to be monitored by CMD & EMEA CONCLUSION Commission legal framework revision on track Better Regulation Key-items put in place handling of variations more efficient, more flexible harmonised system in EU Implementation preparation work ongoing MSs, EMEA, EC -> dedicated working groups to prepare for implementation + give guidance to MAHs Procedural & Classification Guidelines: - Joint effort of EC, EMEA, CMD(h) (v), CHMP, CVMP - Industry input via external consultation and workshops - Final adopted by European Commission in Nov

14 Regulation foresees regular updating of the Guidelines to take account of scientific & technical progress (Art 4(2)) Guidance on ectd and Application form available shortly Further detailed procedural guidance to be published by CMD and EMEA (e.g. BPG updates, PAG updates, SOP, templates) Prepare for full implementation by 1 Jan 2010! Thank you Hilde Boone EMEA Regulatory Affairs hilde.boone@emea.europa.eu

15 Abbreviations ASMF BPG CAP CMD(h)(v) CMS CP CxMP DCP DDPS EC ectd EMEA EU Active Substance Master File Best Practice Guide Centrally Authorised Product Coordination Group for Mutual Recognition and Decentralised Procedures (human) (vet) Concerned Member State Centralised procedure Committee for Medicinal Products for Human/Veterinary Use DeCentralised Procedure Detailed Description of the Pharmacovigilance System European Commission Electronic Common Technical Document European Union 29 FUM ICH MA(A) MAH MRP MS NAP NEES PAG PhVig PMF S/E RMS SOP SPC USR VAMF VRIT Follow-up Measures International Conference on Harmonisation Marketing Authorisation (Application) Marketing Authorisation Holder Mutual Recognition Procedure Member State Nationally Authorised Product Non ectd Electronic Submission Post-Authorisation Guidance Pharmacovigilance Plasma Master File Safety/Efficacy Reference Member State Standard Operating Procedure Supplementary Protection Certificate Urgent Safety Restriction Vaccine Antigen Master File Variation Regulation Implementation Team 30 15

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