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Croatia Drug Product Registration

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Croatia Drug Product Registration

Safeguarding Public Health Through Comprehensive Regulation

MoH

The Ministry of Health of the Republic of Croatia (Croatian: Ministarstvo zdravstva)

MoH Website

https://www.eunethta.eu/miz/

Regulatory Agency

Agency for Drugs and Medical Devices (HALMED)

Regulatory Agency Website 

https://www.halmed.hr/en/O-HALMED-u/

License Validity

5 Years

Renewal

At least 9 months prior to the expiry of the marketing authorisation.

Local Authorised Representative

yes

Fees

http://www.halmed.hr/en/O-HALMED-u/Usluge-i-cjenik/Cjenik-usluga-HALMED-a/

Procedure for Granting Marketing Authorization

  • In the Republic of Croatia, only pharmaceuticals with a marketing authorization issued by the European Commission (EC) or the Agency for Medicinal Products and Medical Devices (HALMED) may be marketed.
  • HALMED issues a marketing authorisation for medicinal product in the national procedure and common European procedures such as the mutual recognition procedure (MRP) and the decentralised procedure (DCP), whereas the EC issues marketing authorisations in the centralised procedure.
  • Based on scientific evaluation of the medicinal product dossier, a marketing authorisation may be granted only for a medicinal product with established appropriate pharmaceutical quality, safety, effectiveness as well as positive benefit/risk balance.

Marketing authorization procedures for medicinal products

There are four marketing authorisation procedures in the European Union (EU):

  1.  Centralised procedure,
  2. Decentralised procedure,
  3. Mutual recognition procedure
  4. National procedure.

Centralised procedure (CP)

  • In the CP, the scientific evaluation of the medicinal product dossier is conducted by the European Medicines Agency (EMA).
  • The marketing authorization is valid in all EU member states and is given by the European Commission.
  • Experts from each EU member state, including Croatia, are involved in evaluating the efficacy, safety, and quality of pharmaceuticals.
  • CP is required for pharmaceuticals containing new substances intended to treat HIV/AIDS, cancer, diabetes, neurodegenerative diseases, autoimmune diseases, and other immunologic dysfunctions; additionally, it also applies to pharmaceuticals produced using biotechnology processes (e.g., genetic engineering), advanced therapy pharmaceuticals (e.g., gene therapy, somatic cell therapy, or tissue engineering), and orphan pharmaceuticals.
  • In addition, if granting a marketing authorization is in the best interests of EU public health, the CP is possible but not required for pharmaceuticals containing significant therapeutic, scientific, or technological innovation, as well as for generic versions of centrally authorized pharmaceuticals.
  • In the Centralised Procedure, the marketing authorisation application and the medicinal product dossier are submitted to EMA.

Mutual Recognition Procedure (MRP) and Decentralised Procedure (DCP)

  • Both the decentralised procedure (DCP) and the mutual recognition procedure (MRP) depend on the mutual recognition of the scientific evaluation of the dossier conducted by one EU member state. This allows for marketing authorization in all other member states to which the same application was submitted.
  • Croatia can participate in these procedures as a concerned Member State (CMS) or as a Reference Member State (RMS) that directs the process and evaluates the medical product dossier.
  • Depending on how many Member States participate in the process, medicinal products approved through one of these pathways may be marketed in Croatia as well as a few other EU countries.
  • After finalisation of the DCP and MRP procedure, product information including summary of Product Characteristics (SmPC), Package Leaflet (PL) and Labelling have been standardized in all Member States involved in the procedure.

  1. Decentralised Procedure (DCP)

  • The DCP procedure authorizes a medicinal product when no marketing authorization has been granted in the EU, the product does not fall under the mandatory scope of CP, and the applicant plans to simultaneously obtain marketing authorization in multiple EU Member States.
  • DCP is initiated simultaneously in the RMS and in other CMSs in the procedure.
  • Chosen RMS evaluates the medicinal product dossier for the first time, prepares the assessment report and circulates it to all CMSs.
  • CMSs can provide feedback on the draft assessment report distributed on the product’s quality, safety, and effectiveness. and if the assessment verifies that the medical product has a positive benefit/risk balance, Member States may then authorize its marketing on national territory.

  1. Mutual Recognition Procedure (MRP)

  • A pharmaceutical may be authorized under the Mutual Recognition Procedure (MRP) if it has previously received national authorization in one EU member state and the holder of the marketing authorization wants to get the product authorized in other EU member states.
  • In every Member State where a marketing authorization is requested (including the Member State in which the product is authorized), the holder of the marketing authorization applies based on an identical dossier that has previously been approved domestically.
  • The product’s authorized Member State is the RMS and other Member States are included as CMSs in the MRP as per choice of a marketing authorisation holder.
  • During the MRP procedure, the RMS sends the other CMSs its evaluation report of the dossier. If the CMSs agree with the assessment, they acknowledge and authorize marketing in their respective countries.

C.  MRP and DCP Procedures – Specific National Requirements

  • New applications in MRP/DCP
  1. The electronic format (eCTD) for the submission of all for marketing authorisation applications
  2. The full electronic dossier should be submitted via CESP to HALMED.
  • Detailed list of national requirements
  1. Written statement by the future MAH (if not seated in Croatia) naming its local representative seated in Croatia with the contact details,
  2. Evidence that the future MAH has responsible person for Pharmacovigilance seated in Croatia authorised by the Agency or proof that application for his/her approval has been submitted to the Agency (this submission should be separate from the submission for marketing authorisation),
  3. Evidence of fee

National procedure (NP)

The purely national procedure (NP) is initiated when an applicant/future marketing authorisation holder intends to place the pharmaceutical product on the market of only one EU Member State. NP is finalised by granting national marketing authorisation, valid only in the territory of that Member State. (purely national authorization is defined in Article 2 of amended Commission Regulation (EC) No 1234/2008).

 Applications Submission for a marketing authorisation in Croatia via MRP/DCP or NP

  • The Medicinal Products Act (Official Gazette, no 76/13, 90/14, and 100/18) and the Ordinance for granting marketing authorizations for medicinal products (Official Gazette No 83/13, 28/20, and 32/2) specify the application process for granting a marketing authorization in the Republic of Croatia.
  • A natural or legal entity with a seat in the EU must submit the application for a marketing authorization to HALMED.

Pharmaceutical Product Dossier

  • The pharmaceutical product dossier must be submitted with the marketing authorization application.
  • The applicant must submit the dossier in Croatian or English language, prepared in the eCTD format with advanced search possibilities through the dossier (hereinafter: eCTD).
  • The eCTD contains the following:

Module 1: Administrative data and product information

Module 2: Summaries

Module 3: Quality

Module 4: Non-clinical reports

Module 5: Clinical study reports

  • The structure of an individual module of the eCTD is explained in Annex I to the Ordinance.
  • The marketing authorisation holder shall submit the following documents along with the dossier:
  1. Cover letter for application for a marketing authorisation:
    • Should be submitted either in Croatian or English, signed by the applicant’s responsible/ authorised.
    • Template for the cover letter is available in Croatian and in English.
  2. Electronic Application form for marketing authorisation:
    • Should be submitted separately for each pharmaceutical form and strength, completed either in Croatian or English, signed by applicant’s responsible/authorised person.
    • EU electronic Application form (eAF) for marketing authorisation is available under the following link- https://esubmission.ema.europa.eu/eaf/index.html
    • The annexes listed in the eAF (in section Annexed documents/where appropriate)  shall be attached as applicable to the application and the submitted pharmaceutical product dossier.
    • Proof of payment, which includes evidence of payment of the fee(s) for the issuance of a marketing authorization in accordance with HALMEDˈs Fees, is a required attachment to the eAF http://www.halmed.hr/en/O-HALMED-u/Usluge-i-cjenik/Cjenik-usluga-HALMED-a
  1. Specific national requirements:
    • The statement is provided by the future marketing authorization holder who is not seated in the Republic of Croatia regarding the appointment of his local representative seated in the Republic of Croatia and its contact information (name, address, and phone number), if applicable.
    • Evidence that the future marketing authorization holder has a qualified individual for pharmacovigilance who resides in the Republic of Croatia and has been approved by HALMED, or confirmation of an application submitted to HALMED for approval of the person responsible for pharmacovigilance with residence in the Republic of Croatia.

Marketing Authorization Process at HALMED

Validation Phase

  • After submitting marketing authorization application to HALMED, regulatory experts from the Department of Applications Validation, review the application and verify the administrative and regulatory compliance of the pharmaceutical product dossier with the current regulations for medicinal products.
  • In the process of validation, the following is reviewed:
  1. presence of all the components of the application and completeness of the submitted dossier.
  2. The presence and validity of the documents and Module 1 components.
  3. compliance of the filled dossier (in specific parts of Modules 2, 4 and 5) with the proposed legal basis in the application and, where applicable with the specific requirements for the particular group of the medicinal products, according to national and EU regulations as well as relevant guidelines for the medicinal products.
  • When an application is found to have mistaken in the application, HALMED notifies the applicant via Notice on Invalid Application, along with a deadline for finishing the application and dossier.
  • HALMED notifies the applicant as soon as the application proves to be valid.
  • Depending on the type of procedure, the application or dossier is sent from validation to the appropriate Regulatory Affairs Department (either national or MRP/DCP coordination).
  • From the start of the dossier evaluation process until the procedure’s conclusion, regulatory specialists in each coordination oversee and coordinate the application processing.

Assessment or Evaluation of the Dossier

  • The coordinators forward the valid application for the evaluation of the dossier. The evaluation of the dossier is a scientific and critical review on submitted data according to current regulations in Croatia and EU as well as relevant guidelines for the medicinal products (published by EC, CMD(h), EMA, HALMED and other), the latest scientific and technical achievements in manufacturing, quality control, research and development, efficacy and safety  of the medicinal products.
  • Quality Assessment department’s inspector reviews the documentation on the quality of the active substance(s) and finished product.
  • Non-clinical and clinical inspectors at the Department for Safety and Efficacy Assessment review documentation on non-clinical investigations and clinical studies during medicinal product development to establish safety and efficacy.
  • The Department for Pharmacovigilance and Rational Pharmacotherapy inspector also participates in reviewing documentation related to safe use.
  • An assigned inspector scientifically evaluates dossier modules, providing a detailed assessment report that includes a review of each module, a critical analysis of relevant data for forming an opinion on benefit/risk balance, and proposes an opinion on the acceptability/non-acceptability of the evaluated documentation.
  • The report also lists questions for the applicant to address. The pharmaceutical product cannot be approved if the applicant does not provide satisfactory responses to the questions related to a potential serious risk to public health.
  • During this stage, it is possible to request samples and documentation for laboratory testing in the Official Medicines Control Laboratory Division (OMCL) of the HALMED. A crucial component of the quality evaluation report is the testing findings for the samples of pharmaceutical products, together with any potential commentary on these results and the analytical methods used.
  • In addition, every assessment report is reviewed scientifically and critically by another HALMED’s most experienced inspector in certain area.
  • The assessment report and dossier are discussed at internal inspector working groups to ensure the highest level of HALMED expertise, consistency of assessments and opinions, and harmonized interpretation of regulations and guidelines by all assessors. This is particularly important in cases where the assessor responsible for reviewing the assessment report has a different opinion from the assessor who prepared the assessment report or evaluated the documentation.
  • If additional specific knowledge is required for the evaluation of the dossier, HALMED may consult with external experts strictly specialised in certain areas and request an opinion of the external expert on the evaluation of the dossier.
  • The expert and regulatory evaluation of the proposed SmPC, PL, and labeling, in compliance with the supplied dossier and the existing rules, is also a crucial component of the evaluation.

Medicinal Products Committee

  • The authorized inspector notifies the relevant Regulatory Affairs department coordination immediately after the evaluation is completed.
  • After all assessment reports are completed, the concerned coordinator organizes a meeting with all assessors participating in the dossier evaluation.
  • The inspector’s comments are debated in a multidisciplinary manner during the meeting, and the application for a marketing authorization is referred to the Medicinal Products Committee following the meeting.
  • The Committee is an expert body under HALMED that reports to the Head of HALMED, providing recommendations for approval or rejection of marketing authorization, renewals, and modifications.
  • At the Committee sessions, final decisions and queries for the applicants are determined. Meeting minutes are recorded, and they are approved 2 days following the meeting.

Questions/objections

If submitted data is insufficient for a positive quality, safety and efficacy assessment of the medicinal product, after the meeting of the Committee and endorsement of minutes, concerned coordination addresses the questions/objections to the applicant about deficiencies in the application/dossier according to the Committee’s conclusions, asking for additional information/documentation or appropriate justification.

Finalisation of the procedures

  • After submission and evaluation of the necessary additional documents, the process concludes with the granting or rejection of a marketing authorization.
  • HALMED will decide whether to give marketing authorization with the authorized SmPC, PL, and labeling if, following the evaluation of the response, a favorable view about the benefit/risk balance is achieved. At that point, the medical product may be sold in Croatia.
  • Apart from the decision to provide marketing authorization, HALMED has the option to ask the holder of marketing authorization for actions that he must do following the issuance of the authorization (Follow-up measure/FUM, or Post-authorization measures/PAM).
  • The medical product’s benefit/risk ratio shouldn’t be affected by meeting follow-up requirements after receiving a marketing authorization, nor should they be a prerequisite for putting the product on the market.
  • To get a final opinion on the quality, safety, and effectiveness evaluation, only information that was unavailable to the applicant throughout the marketing authorization procedure may be requested.
  • The application for granting a marketing authorization must be reexamined by the Committee if, following the evaluation of the answer, it is determined that the benefit/risk balance is unfavorable, and the permission must be denied.
  • HALMED renders a judgment on the denial of the marketing authorization and notifies the applicant of the reasons for the rejection if the Committee approves the proposed opinion on the rejection.

Medicinal Products Database

  • The HALMEDˈ website (http://www.halmed.hr/en/Lijekovi/Baza-lijekova/) contains information on the approved pharmaceuticals, such as the approved SmPCs, PLs, and the public assessment reports (published for pharmaceuticals for which the applications for granting a marketing authorization were submitted after Croatia’s EU accession).
  • The public evaluation report is a brief summary of the comprehensive evaluation reports contained in the dossier. It excludes secret information and offers transparent, easily accessible information intended for the general public.

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