Medicinal Products

Instructions for submitting an application for dossier upgrading

Instructions for Submitting an Application for Dossier Upgrading
(Version 1, 19th November 2012)

These instructions for submitting an application for dossier upgrading are amending the previously published information in the section "Upgrading of Documentation for Medicinal Products" (Version 2, 1th September 2012).

In accordance with the previously published information, the submission of an application for dossier upgrading is not mandatory for medicinal products whose:

  1. I. marketing authorisations have been granted by the centralised procedure according to Regulation (EC) No. 726/2004
  2. II. marketing authorisations have been granted or whose documentation has been updated according to the Ordinance on special conditions for placing medicinal products authorised in the Member States of the European Union on the market of the republic of Croatia (Official Gazette No. 10/08), which means for products whose notification on the outcome of granting the marketing authorisation or procedure for retrospective inclusion into nCADREAC have been granted by HALMED (according to the Annex II to the New Collaboration Agreement between Drug Regulatory Authorities in Central and Eastern European Countries/nCADREAC, Annex 2).
  3. III. marketing authorisations have been granted according to the current Croatian pharmaceutical legislation (applications for granting marketing authorisations received on 11th October 2008 and later) whose documentation is considered in compliance with Directive 2001/83/EC.

For medicinal products under the above mentioned Paragraphs II and III, for which the documentation is considered upgraded according to the current Croatian legislation and the Directive 2001/83/EC, marketing authorisation holders were obliged by 30 September 2012 to upload to HALMED's database, by using a web application, the following data:

  • requested data in the application part relating to upgraded medicinal products
  • data about the planned implementation/implemented product name in Braille script and planned/implemented readability testing of the package leaflet.

The submission for dossier upgrading is mandatory for all other medicinal products according to deadlines previously published in "Upgrading for documentation for medicinal products" (Version 2, 1th September 2012).

The application for dossier upgrading may be submitted according to the:

  1. Ordinance on rules and methods for granting the marketing authorisation (Official Gazette, Nos. 113/08 and 155/09)
  2. Ordinance on special conditions for granting marketing authorisation in Croatia for medicinal products already authorised in the EU (Official Gazette, No. 10/08)

NOTES for submitting an application for upgrading:

  • The documentation for upgrading is submitted exclusively once, in accordance with these Instructions
  • Applications for upgrading submitted before publishing of these Instructions, have to be updated in accordance with these Instructions. The date of submission for upgrading will be considered the date of submission according to these Instructions and the previously submitted documentation must not be re-submitted, but referred to.
  • The proof of payment of the administration fee for every application for upgrading has to be submitted
  • The applicant is obliged to pay the fees for the documentation upgrading no later than by the end of the procedure.

1. The submission of applications for documentation upgrading according to the Ordinance on the procedure and method for granting the marketing authorisation (Official Gazette, Nos. 113/08 and 155/09)

In order to upgrade the documentation, the marketing authorisation holder is obliged to submit:

1.1. Written request
1.2. Application form for dossier upgrading
1.3. Documentation for upgrading
1.4. Justification of a legal base
1.5. SmPC, PL and labelling, when applicable

It is mandatory to submit the Module 1 for documentation upgrading with the application for upgrading. The content and instructions are available here: (.doc); (.pdf) (in Croatian).

1.1. Cover letter for documentation upgrading

In the cover letter for dossier upgrading, the following data should be specified:

  • Basic product data: the name of the medicinal product, pharmaceutical form and strength, type(s) and size(s) of packaging, (INN in Latin, or other common name), marketing authorisation holder in Croatia and the class of the current MA (or the last issued in the case when the marketing authorisation has expired and the renewal procedure is pending)
  • Type of application: request for documentation upgrading according to the ordinance on the procedure and method for granting marketing authorisations for medicinal products in Croatia (Official Gazette, Nos. 113/08 and 155/09)
  • Legal provisions for documentation upgrading according to the Medicinal Products Act (Official Gazette, Nos. 71/07, 45/09 and 124/11)
  • All necessary annexes attached to the application.

1.2. Application form for documentation upgrading (.doc, .pdf)

The application form for dossier upgrading should be populated:

  • separately for every current marketing authorisation for which the application for dossier upgrading has been submitted (for more MAs, it is possible to fill out one application form only in case when in the renewal procedure, more packaging sizes will be approved in a single marketing authorisation for renewal and in the same time the application for documentation upgrading is being submitted).
  • necessary data, signed by the responsible person of the marketing authorisation holder in Croatia, sealed and submitted in a paper and electronic version (Word version on CD).

1.3. Documentation for upgrading

The following cases for dossier upgrading are possible:

1.3.1. The additional documentation does not need to be provided with the application form - the previously submitted documentation is considered upgraded

The documentation for upgrading is comprised of all the previously submitted data during procedures for granting the marketing authorisation / variation / renewal / or MA transfer, before submitting an application for dossier upgrading according to these Instructions.

The previously submitted documentation does not need to be re-submitted. The above mentioned refers to the documentation provided with already submitted applications for upgrading before these Instructions were published, as well to the documentation previously submitted to the Ministry of Health, taking into account that all documentation is archived in HALMED.

In this case it is necessary to:

  1. provide the "Statement on dossier upgrading" (.doc, .pdf), signed by the responsible person of the marketing authorisation holder in Croatia and sealed
  2. highlight in the Table 1 "The content of the documentation" (.doc, .pdf) the content, which means the current parts of the submitted documentation, of which the marketing authorisation holder disposes and which substantiates the legal provision for dossier upgrading and to which "The statement on dossier upgrading" refers.

    When highlighting the content/parts in the table of the submitted documentation:
    • it is not necessary to highlight the previously submitted documentation in STD format, if replaced completely by the new documentation version in CTD format
    • in case that certain parts of the documentation in STD format are still in effect, hence only certain parts have been replaced by CTD format, it is necessary to highlight for every valid part of the documentation in the table, whether it is in STD and/or CTD format.
    The populated Table 1 "The content of the documentation" has to be submitted in a paper and electronic version (Word version on CD).
  3. provide "The list of pending applications submitted to HALMED" indicating:
    • pending applications, which means applications that have been submitted and have not been resolved by the date of submission for upgrading
    • type of application (variation and/or renewal and/or transfer of MA) the date of submission
    • short description of the variation indicating to which part of the documentation is referred to (indicate when the SmPC and/or PL and/or labelling are changed).
    "The list of pending applications submitted to HALMED" has to be attached to the "Application form for dossier upgrading" in the Part 1.2 of the Module 1.

1.3.2. Documentation for dossier upgrading is comprised from the previously submitted documentation and the additional documentation submitted with the application according to these Instructions

1.3.2.1. Previously submitted documentation

It is necessary to provide documents stated under 1.3.1. of these Instructions.

1.3.2.2. Additional documentation submitted and attached to the application for upgrading:

  1. that does not need to be notified as a variation and can be included in the application for upgrading:
    • o non-clinical and clinical documentation that has been submitted according to the proposed legal provisions for upgrading according to the current Croatian legislation and Directive 2001/83/EC, as amended and the Guidelines of the European Commission and the European Medicines Agency (EMA).
      i.e.:
      • submission of new data/documentation for medicine under Article 15, Paragraph b) of the Medicines Act (well-established use) for which the scope and criteria for bibliographic data, at the time of issue of the first authorisation, were not stipulated as they are in the current Croatian and European legislation or
      • submission of bioequivalence data under Article 15, Paragraph a) of the Medicines Act (generic medicine) or
      • submission of clinical trial results under Article 17, Subparagraph 1, Paragraph a) of the Medicines Act (hybrid) or under Article 14 of the Medicines Act (complete/or "mixed" documentation comprised of bibliographic and clinical trial data)
    • harmonisation of the Summary of Product Characteristics, Package Leaflet and Labelling with the current Croatian legislation
    • changes in the text of the Summary of Product Characteristics and/or Package Leaflet without changing the content (i.e. more appropriate linguistic or scientific terminology)
    • transformation of the package leaflet in a "patient friendly" form and readability testing
    • new versions of earlier submitted documentation parts without changing the content (i.e. internal harmonisation of documents with the manufacturer's quality assurance system or the harmonisation of terminology with the current edition of the Ph. Eur.)
    • providing the name of the product in the Braille script
    • harmonisation of the Summary of Product Characteristics with the Summary of the reference product for medicines undergoing dossier upgrading under Article 15, Paragraph a) of the Medicines Act (generic medicine) or Article 17, Subparagraph 1, Paragraph a) of the Medicines Act (hybrid)
    • harmonisation of the Summary of Product Characteristics/Package Leaflet/Labelling with:
      • European Commission's Decisions in arbitration procedures, available here
      • information about medicinal products of the Coordination Group for MRP and DCP for human medicines/CMDh, available here
      • Community herbal monographs for traditional herbal medicinal products.
    Changes/additions of data that are in compliance with the above mentioned under 1.3.2.2.a) of these instructions should be indicated in the Part 6 of the application form for dossier upgrading (briefly elaborate the changes and specify documentation parts that change/supplement and what are the differences in comparison to the recent authorised data).
  2. that should be notified separately as a variation, cannot be included in the application for upgrading:
    • changes in the documentation content for which a variation application should be submitted under Ordinance on procedure and method for granting the marketing authorisation for medicinal products (Official Gazette, No. 113/08 and 155/09)
    Variations that are notified simultaneously with the application for dossier upgrading under 1.3.2.2. b) of these instructions, should be indicated in "The list of pending applications submitted to HALMED".

"Statement on documentation compliance" that has to be provided with the application for dossier upgrading in the case under 1.3.2. of these instructions should refer to the complete product documentation provided under 1.3.2.1. and 1.3.2.2.

1.3.3. A consolidated documentation should be provided with the application for upgrading - completely or partially

1.3.3.1. Complete consolidated documentation for medicinal product - all consolidated Modules

A consolidated, complete documentation, Modules 2, 3, 4 and 5 (Modules 4 and 5 may be Part III and Part IV + variations/additions in CTD format) that include all authorisations/notified variations and in accordance with the Ordinance on the procedure and method for granting marketing authorisation of medicinal product (Official Gazette, No. 113/08 and 155/09), should be provided with the application for upgrading.

In this case, it is necessary to provide documents under 1.3.1. of these Instructions.

In the case when the consolidated documentation includes all new changes7additions of data with respect to the recent approved/notified variation to HALMED, it is necessary to act in accordance with the Paragraph 1.3.2. of these Instructions, depending on the case that applies to that documentation.

Consolidated Modules 3, 4 and 5 of the documentation must be accompanied by relevant 2.3., 2.4. and 2.5. Parts of the Module 2.

It is necessary to indicate the status and manner of consolidation for every Module under Notes in the Table 1 "The content of the medicinal product documentation".

1.3.3.2. Partially consolidated documentation - certain consolidated Modules

Individual consolidated Modules are provided with the application in which all approved/notified variations are included. Other parts of the documentation are not consolidated, include all previously approved/notified data, though.

The consolidated Module must be accompanied by an appropriate part of the Module 2.

In that case, it is necessary to provide documents listed under Paragraph 1.3.1. of these Instructions.

In case when the consolidated module or new documentation parts include new variations/additions of data with respect to the recent approved/notified variation to HALMED, it is necessary to act according to the Paragraph 1.3.2. of these Instructions, depending on the case that is applicable to that documentation.

It is necessary to indicate the status and manner of consolidation for every Module under Notes in the Table 1 "The content of the medicinal product documentation".

1.4. Justification of legal basis

In the Module 1.5., the marketing authorisation holder should indicate the justification of the legal basis under which the upgrading is requested that should be based on:

  • the content of the parts 2.4. and 2.5 of the Module 2 (Expert overviews) and
  • approved/submitted non-clinical and clinical documentation in Modules 4 and 5 (which means the Part III and IV of the documentation in STD format) whose content should substantiate the legal base under which the upgrading is requested.

Parts 2.4. and 2.5. of the Module 2 should be based on the documentation in Modules 4 and 5 that should clearly indicate that the non-clinical and clinical documentation that they refer to, substantiates the legal base under which the upgrading is requested.

  1. If the previously submitted parts 2.4 and 2.5 of the Module 2 in approved/submitted regulatory procedures reaffirm that the non-clinical and clinical documentation substantiates the legal base under which the upgrading is requested, it is necessary to re-submit it with the application for upgrading (attach copies of previously provided parts 2.4. and 2.5. of the Module 2).
  2. In other case, new parts 2.4 and 2.5. of the Module 2 should be provided with the application for upgrading and the documentation in Modules 4 and 5 updated accordingly.

1.5. Summary of Product Characteristics, Package Leaflet and Labelling

The Summary of Product Characteristics, Package Leaflet and Labelling that are proposed for upgrading:

  1. have not changed with regard to the recently approved documents by HALMED → document proposals do not need to be provided with the application for upgrading, it should be indicated in the application form for upgrading that they are not attached or
  2. have changed with regard to the recently approved documents by HALMED → document proposals should be provided with the application for upgrading, it should be indicated in the application form for upgrading that they are attached hereto. Changes in the document should be highlighted with regard to the recently approved documents by HALMED (by using Track Changes). Documents should be additionally provided in electronic version and on a CD.

1.5.1. Summary of Product Characteristics

  1. The Summary of Product Characteristics should be based on the data contained in the documentation and should be updated with the newest knowledge with respect to safe use and efficacy
  2. For Summaries of Product Characteristics containing active substances for which in the EU referral procedures have been carried out under Articles 29, 30, 31, 35 and 36 of Directive 2001/83/EC ("Community Referral Procedures"), HALMED recommends a harmonisation with the European Commission's Decisions available here and information on medicinal products available on the webpages of CMDh, or here ("Product Information").
  3. SmPC of a generic product should be harmonised with the SmPC of the reference medicinal product approved in Croatia and if the referent product is not approved in Croatia than the Summary of Product Characteristics should be harmonised with the SmPC of the reference medicinal product selected from an EU/EEA Member State. If an European reference medicinal product has been chosen for harmonisation of the SmPC in Croatia and the reference product is approved in Croatia, it should be elaborated in the relevant part under 5.c) of the application form for upgrading.
  4. d. For Summaries of Product Characteristics of (traditional) herbal medicinal products containing active substances described in the Community herbal monograph, HALMED recommends to harmonised with clinical pharmacological data indicated in the respective monograph, available on the webpages of the European Medicines Agency, or here.
  5. e. The SmPC format should comply with the Medicines Act (Official gazette, No. 71/07, 45/09 and 124/11) and the Ordinance on the procedure and manner of granting marketing authorisations (Official Gazette, No. 113/08 and 155/09).

1.5.2. Package Leaflet

  1. Data in the Package Leaflet should be harmonised with the SmPC.
  2. The Package Leaflet should be in compliance with the Medicines Act (Official Gazette, Nos. 71/07, 45/09 and 124/11) and the Ordinance on the procedure and method for granting marketing authorisations for medicinal products in Croatia (Official Gazette, No. 113/08 and 155/09),
  3. The package Leaflet should be in the "patient friendly" format
  4. Readability testing of the Package Leaflet is encouraged either through dossier upgrading or variations according to HALMED's Instructions, Directive 2001/83/EC and European Commission's:
    • "Guideline on the readability of the labelling and package leaflet of medicinal product for human use", revision 1, 12 January 2009".
    • "Guidance concerning consultation with target patient groups for the package leaflet", Article 59(3) and 61(1) of Directive 2001/83/EC as amended by Directive 2004/27/EC
    and information available on the webpages of the CMDh, or here ("Consultation with target patient groups").

1.5.3. Labelling of medicinal products (inner and outer)

  1. 1. The labelling of the medicinal product should be in compliance with the Medicines Act (Official Gazette, Nos. 71/07, 45/09 and 124/11) and the Ordinance on the procedure and method for granting marketing authorisations for medicinal products (Official Gazette, No. 113/08 and 155/09),
  2. 2. The expression of the product name in Braille format is encouraged either through dossier upgrading or a variation in accordance with HALMED's Instructions, Directive 2001/83/EC or European Commission's "Guidance concerning the Braille requirements for labelling and the package leaflet, Article 56a of Directive 2001/837EC, as amended".

2. The Submission of applications for dossier upgrading according to the Ordinance on special conditions for placing the medicinal product in the Republic of Croatia that is authorised in the EU Member States (Official Gazette, No. 10/08)

The application for dossier upgrading according to the Ordinance on special conditions for placing a medicinal product on the market in the Republic of Croatia that is authorised in the EU Member States (official Gazette, No. 10/08) may be submitted by the accession date of the Republic of Croatia to the EU (the validity of the Ordinance).

Applications for dossier upgrading may be made according to that Ordinance for medicinal products authorised in the EU via mutual recognition (MRP) or decentralised procedure (DCP) under Articles 19 and 21 of that Ordinance (the procedure of retrospective inclusion into nCADREAC), for which the following should be provided:

  • Cover letter - indicate data as described under 1.1. and for the type of application indicate: application for dossier upgrading according to the Ordinance on special conditions for granting marketing authorisation in the Republic of Croatia for products authorised in the EU Member States (Official Gazette, No. 10/08),
  • Application form (Annex 1. of the Ordinance on special conditions for granting marketing authorisation in the Republic of Croatia for products authorised in the EU Member States (Official Gazette, No. 10/08). All necessary data should be populated and "Dossier harmonisation for a medicinal product in Croatia with the dossier authorised in the EU should be marked under "1. Type of application".
  • Documentation for the medicinal product under articles 19 and 21 of the Ordinance on special conditions for granting marketing authorisations in Croatia for medicinal products authorised in the EU Member States (Official Gazette, No. 10/08).
Top