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Evaluation and Regulation of Medicines & Health Products. EU Variation Regulations (541/95 and 542/95) Final Proposals. FFUL Lisbon Hilde Boone - EMEA 29 May 2003. Review Initiative. End of 2000 : NL proposal agreed at Pharmaceutical Committee

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evaluation and regulation of medicines health products

Evaluation and Regulation of Medicines & Health Products

EU Variation Regulations(541/95 and 542/95)Final Proposals

FFULLisbonHilde Boone - EMEA 29 May 2003


Review Initiative

End of 2000:

NL proposal agreed at Pharmaceutical Committee

Commission NTA Proposals for Revision of Variation Regulations


  • Reduce workload of Competent Authorities (& industry)
  • Simplify and improve procedures
  • Suitable for enlargement

Initial NTA Proposals

2 Variation Categories:

No AssessmentType 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’


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?


Final NTA Proposals

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

3 Variation Categories:

No AssessmentType IA

notification validity check implementation (‘tell and do’)

Assessment short assessment Type IB(as in current Type I) assessment Type II


Minor Variations

  • 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

  • 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

Minor Variations

  • 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’

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)

Annex I

48 Variation entries*, covering 51 Type IA changes 61 Type IB changes * based on list April 03


Major Variations

  • 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 !


  • 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


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

Other Proposals

  • Safety Type II Variations and USRs: to be implemented within a defined timeframe as agreed with EC/EMEA.
  • Type II: introduction of clock-stop (instead of extensions)
  • Regulation will also apply to VAMF/PMF variations
  • Specific provisions in CP forHuman influenza vaccines(based on current practice in MR procedure)
  • Update of Commission Decision Annexes after Type IA and Type IB: every 6 months
  • Possibility for consequential & parallel variations
  • Harmonised numbering system for MR and centralised variations
Submit variation to all RMS + CMSs

MAH to allocate procedure number in advance

Type IA Variations:

Validitycheck: -> 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

no approval of the variation by the CMS is necessary

“ …. variation shall be deemed to have beenaccepted by all national competent authoritiesof the MSs…”

“….RMS shall informthe other national competent authorities of theMSsconcerned and the MAH….” holder


“ ....each CMS shall, where necessary, amend the MA ...“

MRP-specific issues

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

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

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


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


Next Steps - Finalisation

Agreement at Standing Committee: 3 April 03

Publication in Official Journal: June 03

Finalisation of Application form & Guideline: NTA June 03

Implementation: October 03


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



  • 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
  • easier to prepare notifications
  • more harmonisation, less interpretation
  • smoother validation
  • faster approval and implementation
  • reduction of assessors’ and MSs workload
  • allow better industry planning


  • 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

Next Steps:

  • Prepare for implementation
  • Monitor performance of new Regulations