Variations to products authorised through the Decentralised and Mutual Recognition Procedure

Following approval, a Marketing Authorisation may be varied, for instance, to add a new manufacturing site, to change the method of manufacture or to add a new indication. Variations are either minor Type IA or Type IB, or major Type II, as defined in Commission Regulation 1234/2008. 

This new regulation applies for products authorised through the Centralised Procedure and those authorised through the Decentralised and Mutual Recognition Procedures.  The new variations regulation replaces the former regulations – Regulation EC 1084/2003 (MRP/DCP) and Regulation EC 1085/2003 (centrally authorised products).  The new regulation will apply for applications submitted from January 2010 for all products authorised through European procedures.

These new regulations have introduced several new concepts, such as the possibility of a ‘tell and do’ procedure, where certain types of variations can be implemented immediately upon notification.  Other new possibilities include that of grouping of variations belonging to one marketing authorisation holder, worksharing and new timelines.

Detailed information on the submission of variations through the MRP and DCP can be found in the Variations Section on the CMDh website.  The European Commission has also published updated guidance documents, categorization guidelines and an application form to cover variations submitted in accordance with Regulation EC 1234/2008.

National Variations

Applications for variations to a Marketing Authorisation which was issued as a result of a national procedure are to be made directly to the Medicines Authority.  The new variations directive 2009/53/EC is applicable for variations submitted for products authorised through the national procedure.  The new regulations are applicable for national products as from 20 January 2011.

According to this Directive, the requirements for national applications will be similar to those for European procedures and worksharing and grouping of variations will also be possible. 

National variation applications for products with a marketing authorisation authorised through the PMA/MA process and their line extensions should be submitted using the new variation application form found on the EudraLex - Volume 2 - Pharmaceutical Legislation Notice to applicants and regulatory guidelines medicinal products for human use.

Correct submission of documents

It is important that application forms are filled in correctly and that all the documents that should be appended to the application form are also submitted.  These include a signed paper copy of the application form and covering letter and all the documents as per the categorization guidelines.

Please also make sure that:

•          The Product Information (SmPC, Package Leaflet and labelling) is always the latest approved and should contain the changes as proposed in the scope of the variation application form.

•          The product information is track changed to facilitate the review process

•          No other changes that are not covered by the variation application are included in the product information. If there are administrative changes, these should be written in the ‘present and proposed section’ of the application form

•          The SmPC submitted is in an editable word format

•          Type II variations are accompanied by a clinical and/or quality expert statement.

•           

Fees for Variations

Fees charged for variations can be found in the Medicines Authority (Fees) Regulations, (p.p. 7478-7483).

Fees for variations for products authorised both through the Mutual Recognition Procedure or Decentralised Procedures with Malta as Concerned Member State, are included in the annual fee of each product.  

No fees are due for variations for products authorised through the national procedure (PMA/MA and their line extensions) as these are also included in the annual fees for each authorised product.  However, the national variation fees (as per Schedule 2 of the Fees legal notice – Medicines Authority (Fees) Regulations) are applicable when the variation has not been approved in the country of source at the time of submission.  A copy of the approval should therefore be included with the application form.  If the approval is not present at time of submission of the variation application, the variation fees as outlined in Schedule 2 of the Legal Notice on fees are due, irrespective of type of variation. 

If the variations are only applicable for the product on the market in Malta, the fees for national variations should always be paid. 

Application forms must be accompanied by an approval letter or a proof of payment on submission.  Lacking either, the applications will not be processed.

Fees for variation applications through the MR and DC procedures with Malta as Reference Member State (RMS), and for variations for national products NOT authorised through the PMA/MA process (or their line extensions) are charged as per the current Fees Regulations. 

Fees for grouped variations

When submitting a group of variations, the fee of the highest variation in the group should be paid, irrespective of the number of variations in the group.  Acceptable groupings are only those listed in Annex III of the regulation.  Examples are given in the CMDh guideline on acceptable groupings:

http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Variations/CMDh_173_2010_Rev3_Clean_2011_04.pdf.

A new fees proposal to cover variation applications in accordance with the new legislation will be announced at a later date.

Notification for changes to Labelling and Package Leaflets in accordance with Article 61(3) of Directive 2001/83/EC (Regulation 8(3) of the Medicinal Products (Packaging and Labelling) Regulations

Article 61(3) of Directive 2001/83/EC states that:

“All proposed changes to an aspect of the labelling or the package leaflet covered by this Title and not connected with the summary of product characteristics shall be submitted to the authorities competent for authorizing marketing. If the competent authorities have not opposed a proposed change within 90 days following the introduction of the request, the applicant may put the change into effect.”

Hence, Marketing Authorisation Holders are required to inform the Medicines Authority of all changes made to the labelling (outer and immediate) and package leaflets (PL) of all authorised medicinal product, that are not connected with changes to the Summary of Products Characteristics (SmPC).

For such notification for national products, applicants should make use of the Notification Form for Changes to Labels and Patient Information Leaflets.  This Notification Form should be completely filled in and full colour mock-ups of the proposed final version of the packaging components and package leaflet affected by the change must accompany the notification.

The Notification Form may be used to inform the Medicines Authority of more than one change relating to a product.  A form per product must be filled in. However, the marketing authorisation holder must ensure that all changes implemented are covered by the Guidelines on Notification of Changes to Labelling and Package Leaflets  in accordance with Article 61(3) of Directive 2001/83/EC.  Marketing Authorisation Holders are informed that any changes introduced to the packaging components but not formally notified, or not covered by the Guidance, may render the notification invalid.

Marketing Authorisation Holders should be aware that the responsibility for the information presented on the packaging and in the PL rests solely with the MAH.

This notification process does not apply to parallel imported products and products authorised in line with article 126(a) of Directive 2001/83/EC, as amended.  The appropriate forms, found in the specific sections for each type of application, for notification for a variation, must be used for products authorised through these procedures.

Fees for notification procedures are included in the annual fee of each authorised product.

Information on submission requirements with respect to electronic and paper copies required can be found here.

Last Updated: 3/6/2011