(Version 1, 8 February 2021)
After obtaining a marketing authorisation, the marketing authorisation holder (MAH) is required to follow the latest scientific and technical progress and information on the safety and efficacy of the medicinal product that may affect the benefit-risk balance. During the life cycle of the medicinal product, the MAH must update the conditions/obligations/restrictions granted by the marketing authorisation and approved product information/medicinal product dossier on which a granted marketing authorisation has been based on. Any change/amendment of the information approved by the marketing authorisation shall be submitted as variation.
1. Definition of variation
Variation to the terms of a marketing authorisation are set out in Article 50 of the Medicinal Products Act (Official Gazette No. 76/13., 90/14., 100/18., hereinafter: the Act) and Commission Regulation (EC) No. 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products, as amended (hereinafter: the Variations Regulation). The Variations Regulation is in force in all EU Member States and applies to all marketing authorisations, granted by NP, MRP/DCP and CP procedures (details on marketing authorisation procedures could be found in the HALMEDˈs instruction Marketing authorisation procedures).
The definition of "Variation to the terms of a marketing authorisation" or "variation" and the types of variation are stipulated by Article 2 of the Variations Regulation.
2. Application for variation
The application for variation should be submitted by the MAH to the HALMED. When submitting a variation, the MAH should classify a variation in accordance to the current Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of amended Commission Regulation (EC) No 1234/2008 and on the documentation to be submitted pursuant to those procedures (hereinafter: the Classification Guideline), drawn up in accordance to Article 4 of the Variations Regulation. The Classification Guideline is intended to facilitate the interpretation of the Variations Regulation, provide details on the application of the relevant variation procedures and details of the classification of variations into the categories as defined in Article 2 of the Variations Regulation and provides further details on the scientific data/documentation to be submitted for specific variations.
2.1. Elements to be submitted
For the application for a variation, the following documents/documentation should be submitted:
1. Cover letter for variation in Croatian or English,
2. Application form for variation completed in Croatian or English.
EU electronic Application Form (eAF) for a variation is available under the following link eSubmisson/EU Electronic Application Forms.
The annexes listed in the eAF shall be enclosed, as applicable to the application for submitted variation.
Proof of payment is mandatory attachment to the eAF and includes:
- proof of payment of fee(s) for variation(s) procedure(s) according to HALMEDˈs Fees and
- proof of payment of the administrative fee according to the Administrative Fee Tariff.
3. Documentation for variation(s) specified in the Classification Guideline depends on type of variation and the classification of the change.
For type II variation and an unforeseen variation (not classified by the Classification Guideline, nor the classification is recommended under Article 5 of the Variations Regulation), for which documentation are not specified in the Classification Guideline, it is necessary to submit relevant scientific data/documentation supporting the requested variation.
When applying for a variation to a marketing authorisation in MRP/DCP, the MAH should follow the "Best Practice Guides (BPGs) for the Submission and Processing of Variations in the Mutual Recognition Procedure” of the Coordination Group for MRP and DCP (hereinafter: CMD(h)), as well as other guides/instructions published on the CMD (h) website in the section "Procedural Guidance/Variations". HALMED also follows these guides/instructions when processing applications for variations to the national marketing authorisation, and recommends to the MAHs to use them when applying for purely national variations.
2.2. Grouping of variations
The conditions for acceptable grouping of variations when submitting grouped application for several variations are laid down in Article 7 and Annex III of the Variations Regulations. HALMED recommends to the MAHs to use CMD(h) guide "Examples for acceptable and not acceptable groupings for MRP/DCP products" and EMA’s document "Grouping of variations: questions and answers", as detailed instructions on the acceptable grouping of variations.
2.3. Questions and answers
HALMED also recommends to the MAHs to follow questions and answers that the CMD(h) continuously updates and publishes in the document Variations/Questions & Answers, providing additional clarifications useful for submitting application for variations.
2.4. Variations following referrals, PSUSA procedure and PRAC recommendations on safety signals
For variations that are the result of the referral procedure outcome, an application should be submitted in accordance with the Instructions for Variation Application after Referral, and for variations that are the result of PSUSA procedure, an application should be submitted in accordance with the instruction Instructions for Variation Applications Following the Outcome of the PSUSA Procedure. Variations based on the PRAC recommendation following the safety signal assessment should be submitted according to the instruction Variation Applications - PRAC Safety Signals. These relevant instructions are continuously updated with the latest adopted procedure outcomes/recommendations.
3. Recommendation for classification of unforeseen variations
For unforeseen variation, which is not classified by the Classification Guideline and for which no recommendation for classification has been given under Article 5 of the Variations Regulation, a request for a recommendation of a classification from a MAH may be submitted to the relevant authority prior to submission of the variation. For detailed instructions on submission request for a recommendation on classification of variation, the MAHs should follow the instructions published on the CMD(h) websites, Best practice guide on CMD(h) recommendations on unforeseen variations and Art.5 on Unforeseen Variations.
The recommendation on classification of variations given via this procedure under Article 5 is consistent with the Classification Guideline and harmonised among all EU Member States. These recommendations, published on the CMD(h)ˈs website in document CMD(h) Recommendations for classification of Unforeseen Variations according to Article 5 of Commission Regulation, should be taken into consideration for classification of variations prior the submission, in addition to the Classification Guideline.
4. Change in prescription and dispensing status of a medicinal product
Change in prescription status ("subject to medical prescription” to "not subject to medical prescription") under Article 33 of the Ordinance, and change of dispensing status of medicinal products ("pharmacy” to "pharmacy and specialised retail stores”) under Article 34 of the Ordinance are not covered by the Variations Regulation and the Classification Guideline, hence, these changes are regulated nationally. When submitting the application for these changes, it is necessary to follow HALMED's recommendations on the classification published in instruction Terms for approval of the change in prescription and dispensing status. The application for the change must include all elements mandatory for any other variation application, together with the documentation supporting the change submitted according to Article 33 or Article 34 of the Ordinance and HALMEDˈs recommendations on the classification in above referred instruction.
These changes may refer to NP and MRP/DCP marketing authorisations. In the case of the MRP/DCP authorisations, the variations applications should be submitted to the competent authority of the Member State where the changes are applicable and these variations are processed nationally.
5. Change under Article 36 of the Ordinance
Changes under Article 36 of the Ordinance (corresponding to the notification for product information amendment under article 61(3) of Directive 2001/83/EC) are not covered by the Variations Regulation/the Classification Guideline and relate to changes of the package leaflet and/or labelling and/or mock-up of the outer/inner packaging of the medicinal product, which is not connected with change of the summary of product characteristics.
An application for a change under Article 36 of the Ordinance (Article 61 (3) of Directive 2001/83/EC) should be submitted by the MAH to the HALMED and/or the Member State’s competent authority where the change is applicable.
The application must be accompanied by the following:
1. Notification form for notification for product information amendment under article 61(3) of Directive 2001/83/EC, published on the CMD(h) website in section 61.3 Procedure to notify the change under Article 36 of the Ordinance, completed in Croatian or English; the notification form is used for NP and MRP/DCP marketing authorisations.
Proof of payment is a mandatory attachment to the Notification form and includes:
- proof of payment fee(s) for change(s) under Article 36 according to HALMEDˈs Fees and
- proof of payment of the administrative fee.
2. documents/documentation in accordance with Article 36 of the Ordinance supporting the requested change.