The Worksharing Procedure for Variations for National Marketing Authorisations in the EU
Did you know that Article 20 of Commission Regulation (EC) N° 1234/2008 (the ‘Variations Regulation’) allows for a Marketing Authorisation Holder to submit the same Type IB or Type II variation, or the same group of variations affecting more than one marketing authorisation from the same Marketing Authorisation, in one application?
In this article we answer 4 important questions related to the worksharing concept.
- What are the 4 types of changes that can be put through in the worksharing procedure?
- What do you need to include in your letter of intent?
- What is the most important part of the letter of intent?
- What is the most significant advantage of using the worksharing method?
Applicants belonging to the same mother company or group of companies and applicants having concluded agreements or exercising concerted practices concerning the placing on the market of the medicinal products concerned, have to be taken as ‘the same Marketing Authorisation”.
In order to avoid duplication of work one member state performs the evaluation on behalf of all.
Where at least one of the concerned marketing authorisations has been authorised via the centralised procedure, the Agency will be the ‘reference authority’. In all other cases, a national competent authority chosen by the Coordination Group, taking into account the recommendation of the holder, will act as the ‘reference authority.
Based on Articles 7 and 20 of the Variations Regulation, when a group of variations only consists of type-IA or -IAIN variations affecting several marketing authorisations, this is considered as a ‘group’ of variations and not a ‘work-sharing’ procedure. However, it is possible to include a group of type-IA and -IAIN variations with a type-IB or a type-II variation, which is submitted for a work-sharing procedure. In such cases, the review of the type-IA or -IAIN variation will be performed as part of the work-sharing procedure.
In order to benefit from a work-sharing procedure, it is required that the same changes will apply to the different medicinal products concerned, with either no or limited need for assessment of a potential product-specific impact. Therefore, where the ‘same’ changes to different marketing authorisations require the submission of individual supportive data sets for each medicinal product concerned, which each require a separate product-specific assessment, such changes will not benefit from work-sharing.
The principle of the work-sharing procedure is the same as the Mutual Recognition/De-centralised procedures, i.e. if the same information is to be assessed by more than one competent authority, one competent authority in the EU should be able to do the assessment of the variation for all impacted countries. In addition to cutting down on un-necessary work by the competent authorities, it encourages the MA holder to harmonise the Chemistry, Manufacturing and Controls Section of the dossier where possible in EU markets.
If the applicant has a harmonised dossier in more than one EU market they could request the dossier to be converted to a de-centralised rather than nationally approved dossiers in the relevant markets. This may or may not suit the MA holder’s strategy for future changes so this has to be carefully considered in advance.
The following types of changes may be put through the work sharing procedure:
- Quality (any changes to the chemistry, manufacturing and controls section of the dossier).
- Changes to the active-substance master file – if companies are not on the same group of companies but agree to put through an application for worksharing to the same CMDh meting this will facilitate supply chain management for both the API and formulation manufacturers.
- Update of the Certificate of European Pharmacopeia. Classifications for updated CEPs range from a Type 1AIN to a 1B, but CEPS can be put through the work-sharing procedure as the assessment of whatever change led to the updated CEP has already been assessed by EDQM.
- Revision of test method for the active substance.
A Letter of Intent is prepared by the Applicant and submitted to either the CmDH for human medicines or the CmVH for veterinary medicines as appropriate.
The committees meet every 2 months so the application letter should be submitted as early as practicable in order to get on the agenda, but at least 3 months in advance of the planned submission date.
The letter of intent outlines the following:
- types and scope of variations;
- overview of MAs concerned;
- explanation that all MAs belong to the same MAH;
- explanation / justification for suitability of worksharing;
- rapporteurs’ reference Member States (RMSs) and national competent authorities of the medicinal products concerned, if applicable;
- MAH target submission date;
- MAH contact person for the work-sharing procedure.
The MAH must submit the variation application for work-sharing at the latest by the recommended submission dates published under submission dates.
The justification for use of the work-sharing procedure is the most important part of the letter. Article 20 of Commission Regulation (EC) No 1234/2008 and
CMDh/173/2010/ Rev.10, July 2013 (EXAMPLES FOR ACCEPTABLE AND NOT ACCEPTABLE GROUPINGS FOR MRP/DCP PRODUCTS) should be cited in the justification.
This should include a common cover letter and application form, together with separate supportive documentation for each medicinal product concerned and revised product information (if applicable) for each medicinal product concerned.
One common cover letter, clearly indicating that the application is submitted for a work-sharing procedure together with a short overview of all medicinal products concerned, with their respective Rapporteurs and RMS’s, as well as an overview of the submission format for the different products, if applicable . Where MRP/DCPs are part of the work-sharing procedure, the MAH should also include a confirmation that the work-sharing applications have been submitted to all Member States where the products concerned are authorised (= RMSs and CMSs) and that the relevant national fees have been paid. A formal letter with the work-sharing applicant and contact person for the work-sharing procedure should be provided with the work-sharing application. In addition to the common cover letter a national cover letter is required in the national language. So for work-sharing applications there are typically 2 cover letters in the submissions.
One completed EU variation application form, listing all medicinal products concerned and declaring all variations included in the group in the section ‘type of changes’, as well as a justification for the proposed work-sharing (and grouping if applicable) in the ‘precise scope and background’ section of the application form. The response from the Agency on the acceptability of the work-sharing application, further to the submission of the letter of intent should be attached to the application form.
Supportive documentation for each product (including the revised summary of product characteristics, labelling and/or package leaflet, if applicable). This will allow the Agency and the national competent authorities to update the dossier of each marketing authorisation included in the work-sharing procedure with the relevant amended or new information.
Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the need for the provision of mock-ups should be discussed with the Agency on a case-by-case basis.
Even though the main body of the procedure is the work-sharing the approvals still have to be issued nationally, and it is in this national phase that any printed packaging materials and updated SmPCs would be submitted.
In general, variations submitted for work-sharing will follow the 60-day evaluation timetable of Type II variations and weekly-start timetables may apply to the assessment following the same principles as those applied to the assessment of Type II variations. The 60-day period may be reduced having regard to the urgency of the matter, particularly for safety issues, or may be extended to 90 days for Type II variations concerning changes or additions to the therapeutic indication. At day 60 of the procedure either the final assessment report or an assessment report with questions/requests for changes is issued by the assessing competent authority. The CMS’s have till day 80 to add their questions/ requests for changed. Day 90 is the commencement of national phases. For the applicant to respond to questions or provide updated CMC documents there is a clock- stop.
One significant advantage of the work-sharing procedure is that there is a time-table. For the assessment of Type 1B and Type II variations which are submitted nationally many competent authorities in the EU do not have a time-table and this can make the implementation of a change which impacts a lot of markets very difficult from a supply chain perspective.
This is the main advantage of the procedure although depending on the markets, there may also be some cost savings as some competent authorities charge a smaller fee as their assessment is based on the assessment of the RMS.
One “dis-advantage” is that the application will receive a very thorough review from the assessing competent authority as they are performing the assessment of all the other impacted member states. Expect a very thorough review and don’t cut corners!
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