Evaluation and Regulation of Medicines & Health Products

The European Agency for the Evaluation of Medicinal Products1

FFUL Lisbon Hilde Boone - EMEA29 May 2003

EU Variation RegulationsEU Variation Regulations(541/95 and 542/95)(541/95 and 542/95)

Final ProposalsFinal Proposals

Evaluation and Regulation of Medicines & Health Products


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 InitiativeReview Initiative


Initial NTA ProposalsInitial NTA Proposals

2 Variation Categories:

No Assessment Type 0notificationvalidity checkimplementation (‘tell and do’)

Assessmentas in current Type II

Reclassify Type I variations over both categories

+ no longer ‘Type I following Type II procedure’


Initial NTA ProposalsInitial 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?


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 ProposalsFinal NTA Proposals



3 Variation Categories:

No Assessment Type IAnotificationvalidity checkimplementation (‘tell and do’)

Assessmentshort assessment Type IB (as in current Type I)

assessment Type II


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 VariationsMinor 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 - 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 -> implementif comments -> extend by 30 days

- (EMEA) positive or negative ‘Notification’



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)


1. Change in the colouring system or the flavouring system currently used in the finished product

Conditions to be fulfilled

Documenta-tion to be supplied

Procedure type

2. a) Reduction or deletion of one or more components of the

3. 1. Colouring system 1, 2, 3, 4, 7 1, 2, 3 IA 4. 2. Flavouring system 1, 2, 3, 4, 7 1, 2, 3 IA 5. b) Increase, addition or replacement of one or more components of the

6. 1. Colouring system 1, 2, 3, 4, 5, 6, 7

1, 2, 3, 4, 5 IB

7. 2. Flavouring system 1, 2, 3, 4, 5, 6, 7

1, 2, 3, 4, 5 IB

Annex IAnnex I

48 Variation entries*, covering 51 Type IA changes61 Type IB changes

* based on list April 03


1. Conditions 2. 1. No change in functional characteristics of the pharmaceutical form e.g. disintegration,

dissolution profile. 3. 2. Any minor adjustment to the formulation to maintain the total weight should be made by

an excipient which currently makes up a major part of the finished product formulation. 4. 3. The finished product specification has only been updated in respect of

appearance/ odour/ taste and if relevant, deletion or addition of identification test. 5. 4. Relevant stability studies (long-term and accelerated) in accordance with the relevant

guidelines have been started with at least two pilot scale or industrial scale batches and at least 3 months satisfactory stability data are at the disposal of the applicant and assurance that these studies will be finalised. Data shall be provided immediately to the competent authorities if outside specifications or potentially outside specification at the end of the approved shelf life (with proposed action). In addition, where relevant, photostability testing should be performed.

6. 5. Any new proposed components must comply with the relevant directives (e.g. Directive 78/ 25/ EEC for colorants, Directive 88/ 388/ EEC for flavours).

7. 6. Any new component does not include the use of materials of human or animal origin for which assessment is required of viral safety data or of compliance with the current Note For Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products.

8. 7. Biological products for which the colouring or flavouring agent are important for the oral uptake by target species, are excluded

9. Documentation 10. 1. Amended pages of Part II A, II B, II C2, II E1 or equivalent in the CTD-format (including

identification method for any new colorant, where relevant) and IIF or equivalent in the CTD-format (if appropriate, where the end-of-shelf life specifications have been updated)

11. 2. The batch numbers of the batches used in the stability studies should be indicated 3. Sample of the new product, where applicable (see Notice to Applicants Requirements for

samples in the Member States) 4. Either a Ph. Eur. Certificate of Suitability for any new component of animal or human

origin susceptible to TSE risk or, where applicable, a document providing information (name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, use of the material) of any materials falling within the scope of the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathies via Human or Veterinary Medicinal Products. For the Centralised Procedure, this information should be included in an updated TSE table A (and B if relevant). For Veterinary Medicinal Products an additional risk assessment is required for products intended for use in TSE-susceptible species.

5. Data to demonstrate that the new excipient does not interfere with the finished product specification test methods (if appropriate).


Major VariationsMajor 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 !


ExtensionsExtensions

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



List Timeframe

Minor Variation Type IA Annex I 14 days

Type IB Annex I 30 days

Major Variation Type II - 60 days

Extension Extension Annex II 210 days

Category


Other ProposalsOther 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 ProposalsOther 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 for Human 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:

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 issuesMRP-specific issues


• 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 ...“



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



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



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 Variationswith timetables for - safety changes

- ‚normal‘ variations- indications



WP / Industry ConsultationWP / 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 - FinalisationNext 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 / CPMPImplementation 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

CONCLUSIONSCONCLUSIONS

easier to prepare notificationsmore harmonisation, less interpretationsmoother validationfaster approval and implementationreduction 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

CONCLUSIONSCONCLUSIONS

Next Steps:• Prepare for implementation• Monitor performance of new Regulations

Documents

Evaluation and Regulation of Medicines & Health Products