Procedure for Granting Marketing Authorisation
(Version 2, 8 February 2021.)
Only a medicinal product having a marketing authorisation granted by the Agency for Medicinal Products and Medical Devices (HALMED) or the European Commission (EC) may be placed on the market in the Republic of Croatia (hereinafter: Croatia).
HALMED grants 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 grants marketing authorisations in the centralised procedure.
Based on scientific assessment of the medicinal product dossier, a marketing authorisation may be granted only for a medicinal product with established appropriate pharmaceutical quality, safety and efficacy and positive benefit/risk balance.
The scientific assessment is based on defined criteria and norms/standards laid down in Croatian and European medicinal product regulations, regulatory and scientific guidelines on medicinal products, and the latest scientific findings.
Marketing authorisation procedures for medicinal products:
There are four marketing authorisation procedures in the European Union (EU):
- centralised procedure,
- decentralised procedure,
- mutual recognition procedure and
- national procedure.
The following sections describe these procedures and provide instructions for submitting respective applications.
In the centralised procedure (CP), the scientific assessment of the medicinal product dossier is conducted by the European Medicines Agency (EMA). The marketing authorisation is granted by the EC and is valid for all EU Member States. Experts from all EU Member States, including Croatia, participate in the assessment of quality, safety and efficacy of medicinal products.
CP is mandatory for medicinal products with new active substances for treatment of HIV/AIDS, cancer, diabetes, neurodegenerative disorders, autoimmune disorders and other immunologic dysfunctions, viral diseases; and also for medicinal products manufactured by biotechnology procedures (i.e. genetic engineering), advanced therapy medicinal products (gene therapy, somatic cell therapy or tissue engineering) and orphan medicinal products. In addition, the CP is possible, but not mandatory for medicinal products with a significant therapeutic, scientific or technical innovation or granting of a marketing authorisation is in the EU public health interest, as well as for generics of centrally authorised medicinal products.
More information on centrally authorised medicinal products and how to get access to their relevant data are available on the EMA’s website in the Medicines/Search, or in HALMED’s Medicinal Products Database.
Submission of marketing authorisation application
In the CP, the application for marketing authorisation and the medicinal product dossier are submitted to EMA. More information on the centralised procedure, submission of the application and evaluation process are available on EMA’s website on Marketing authorisation.
Mutual recognition procedure and decentralised procedure
Mutual recognition procedure (MRP) and decentralised procedure (DCP) are based on mutual recognition and recognition of the scientific assessment of the dossier performed by one of the EU Member States, for the purposes of granting marketing authorisation in all other member states where the same application has been submitted. In these procedures, Croatia may act as a Reference Member State (RMS) that leads the procedure and assesses the medicinal product dossier or may participate in the procedure as concerned Member State (CMS). The medicinal product authorised via one of these procedures may be placed on the market in Croatia and several EU Member States, depending on the number of Member States involved in the procedure.
DCP is a procedure for authorising a medicinal product used in case no marketing authorisation has been granted for a medicinal product in the EU, the product not falling within the mandatory scope of CP and the applicant intends to obtain a marketing authorisation in more than one EU Member State at the same time. DCP is initiated simultaneously in the RMS and in other Member States that are CMSs in the procedure. Chosen RMS assesses the medicinal product dossier for the first time, prepares the assessment report and circulates it to all CMSs. CMSs can actively comment on the circulated draft assessment report on the quality, safety and efficacy, and if the assessment confirms a positive benefit/risk balance of the medicinal product, Member States can grant a marketing authorisation on their national territory.
MRP is a procedure for authorising a medicinal product after the product has already been nationally authorised in one EU Member State, and a marketing authorisation holder intends to obtain a marketing authorisation for the product in other EU Member States. The marketing authorisation holder submits an application based on an identical dossier already authorised nationally, in all Member States where a marketing authorisation is sought (including the Member State in which the product is authorised).The RMS is Member State where the product has been approved, and other Member States are included as CMSs in the MRP as per choice of a marketing authorisation holder. In the MRP procedure, the RMS circulates its assessment report of the dossier to the other CMSs which, if in agreement with the assessment, recognise and grant marketing authorisation in their national territory.
After finalisation of the DCP and MRP procedure, product information (Summary of Product Characteristics (SmPC), Package Leaflet (PL) and Labelling) have been harmonised in all Member States involved in the procedure. The harmonisations of product information are maintained through the procedures of Regulation (EC) No 1234/2008 for the examination of variations and renewals.
Detailed information on the MRP and DCP procedures are available on the webpages of the Co-ordination Group for Mutual recognition and Decentralised Procedure (CMD(h)) in the section Procedural Guidance.
Information for applicants on submission of a MRP/DCP procedure in case Croatia acts as a Reference Member State (RMS) in MRP and DCP Procedures, and a list of the specific national requirements for Croatia in MRP/DCP are published on HALMED’s webpage.
The purely national procedure (NP) for authorising a medicinal product is initiated when an applicant/future marketing authorisation holder intends to place the medicinal 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 definined in Article 2 of amended Commission Regulation (EC) No 1234/2008).
Submission of applications for a marketing authorisation in Croatia via MRP/DCP or NP:
- The procedure for submitting application for granting a marketing authorisation in the Republic of Croatia is stipulated by the Medicinal Products act (Official Gazette, No 76/13, 90/14 and 100/18) and Ordinance for granting marketing authorisations for medicinal products (Official Gazette No 83/13 and 28/20; hereinafter: the Ordinance).
- The application for a marketing authorisation should be submitted to HALMED by a natural or legal person seated in the EU (hereinafter: applicant).
Medicinal product dossier:
The application for granting a marketing authorisation shall be accompanied by the medicinal product dossier. The applicant shall submit the dossier in Croatian or English, prepared in the electronic form of the Common Technical Document with advanced search possibilities through the dossier (hereinafter: eCTD).
The parts of the eCTD are 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 laid down in the Annex I to the Ordinance.
All parts of Modules 1, 2, 3, 4 and 5 shall be submitted with the application unless otherwise is stipulated by the Act and the Ordinance. The content of the individual Module may vary depending on specific requirements related to the nature/specific group of medicinal product and the chosen legal basis for granting a marketing authorisation.
In addition to the dossier, the marketing authorisation holder shall submit the following documents:
- Cover letter for application for a marketing authorisation should be submitted in Croatian or English, signed by the applicant's responsible/authorised person. Template for the cover letter is available in Croatian and in English.
- Electronic Application form for marketing authorisation should be submitted separately for each pharmaceutical form and strength, completed 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 eSubmisson/EU Electronic Application Forms.
The annexes, listed in the eAF (in section Annexed documents/where appropriate) shall be enclosed, as applicable to the application and the submitted medicinal product dossier.
Proof of payment is mandatory attachment to the eAF and includes:
- Specific national requirements:
- statement given by the future marketing authorisation holder that is not seated in the Republic of Croatia about the appointment of his local representative seated in the Republic of Croatia and its contact information (name, address and telephone number), if applicable,
- proof that the future marketing authorisation holder has qualified person for pharmacovigilance with residence in the Republic of Croatia approved by the HALMED, or confirmation of submitted application to the HALMED for approval of the person responsible for pharmacovigilance with residence in the Republic of Croatia.
The application for a marketing authorisation, the medicinal product dossier and all other attachments/documents shall be submitted electronically, via the common European Union application portal Common European Submission Portal/CESP.
Marketing authorisation process at HALMED
After submission of a marketing authorisation application to HALMED, regulatory experts in Department for Validation of Applications review the application and verify the administrative and regulatory compliance of the application/medicinal product dossier with the current regulations for medicinal products.
During the validation phase, the following is reviewed:
- presence of all elements of the application and completeness of the submitted dossier,
- presence and validity of the documents/parts of the Module 1,
- compliance of the submitted 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 and relevant guidelines for the medicinal products.
In case of identified deficiencies in the application, HALMED sends to the applicant a Notice on invalid application, setting out a deadline for completing the application/dossier.
Once the application is considered valid, HALMED informs the applicant. The application/dossier is forwarded from the validation to the relevant coordination of the Regulatory Affairs Department (national or MRP/DCP coordination), depending on the type of the procedure. Regulatory experts in each coordination monitor and co-ordinate on the processing of the application, from the beginning of the assessment of the dossiers until the finalisation of the procedure.
Assessment of the dossier
The coordinators forward the valid application for the assessment of the dossier. The assessment of the dossier is a scientific and critical review on submitted data according to current regulations in Croatia and EU and relevant guidelines for the medicinal products (published by EC, EMA, CMD(h), HALMED and other), the latest scientific and technical achievements in research and development, manufacturing, quality control, safety and efficacy of the medicinal products.
Quality assessors in the Department for Quality Assessment review the documentation on the quality of the active substance(s) and finished product.
Non-clinical and clinical assessors in the Department for Safety and Efficacy Assessment review the documentation on non-clinical investigations in animals, cells, tissues and other models and clinical studies in humans carried out during the medicinal product development phase in order to prove the safety and efficacy.
Assessors in the Department for Pharmacovigilance and Rational Pharmacotherapy are also included in review of the documentation on the safe use (such as documentation on reported adverse reactions, risk management plan etc.).
Allocated assessor scientifically evaluates the Module(s) of the dossier and prepares a detailed assessment report. The assessment report includes a review of the content of every assessed Module of the dossier, a critical overview on the data relevant for the reaching an opinion on the benefit/risk balance and gives proposal for the opinion on acceptability/non-acceptability of the evaluated documentation. In addition, the assessor lists questions in the report that should be addressed to the applicant.
Questions addressed to the applicant may be listed as "Major objections” related to a potential serious risk to public health and/or "Other concerns" as minor deficiencies that require further clarification.
If the applicant has not provided satisfactory responses to the questions related to a potential serious risk to public health, that medicinal product cannot be authorised.
During the assessment phase, it is possible to request samples and documentation for laboratory testing in the Official Medicines Control Laboratory Division (OMCL) of the HALMED. Testing results of the medicinal product samples and possible comments regarding these results and analytical procedures are an integral part of the quality assessment report.
In addition, every assessment report is reviewed scientifically and critically by another HALMED's most experienced assessor in certain area. In the case when the opinion of the assessor in charge of reviewing the assessment report differs significantly from the opinion of the assessor who evaluated the documentation/prepared the assessment report, or in the case of very complex issues, the dossier/assessment report is discussed at the internal assessors working groups to ensure the highest level of expertise in HALMED, consistency of the assessments and opinions, as well as harmonised interpretation of regulations and guidelines by all assessors.
If additional specific knowledge is required for the assessment of the dossier, HALMED may engage external experts strictly specialised in certain areas and request an opinion of the external expert on the assessment of the dossier.
In addition, an integral part of the assessment is expert and regulatory review of the content and format of the proposed SmPC, PL and labelling, in accordance with the submitted dossier and the current guidelines.
Medicinal Products Committee
After finalisation of the assessment, the allocated assessor informs the concerned coordination of the Department for Regulatory Affairs. After all assessment reports have been completed, the concerned coordinator organises a meeting of all assessors involved in the evaluation of the dossier. At the meeting, the opinions of the assessors are discussed multidisciplinarily and, after the meeting, the application for granting a marketing authorisation is referred to the Medicinal Products Committee (hereinafter: Committee).
The Committee is an expert body of the HALMED responsible for its work to the Head of HALMED and gives him proposals of the opinions for granting or rejection of the marketing authorisation, renewals and variations (in cases defined by HALMEDˈs standard operating procedures). The work of the Committee is organised in the meetings that are held every week, schedule of the meetings is available here.
Permanent assembly of the Committee consists of HALMED’s expert employees. If necessary, meetings are held with the Extended assembly of the Committee when, in addition to members of the Permanent assembly, external experts are invited at the meeting in cases where a specific expertise is required for discussion and opinion making on the assessment of a particular application. External experts are mostly medical doctors, specialists in certain therapeutic areas, who have specific practical knowledge and experience in the treatment of indications concerned, thus contributing to the quality of the assessment.
Final conclusions and questions to be addressed to the applicants are defined at the meetings of the Committee. Minutes are being taken at meetings and these minutes are endorsed within 2 days after the meeting. The minutes, excluding confidential information, may be found here.
If submitted data are not sufficient 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, requesting to provide additional information/documentation or appropriate justification.
Finalisation of the procedures
When the requested additional documentation has been submitted and assessed, the procedure is finalised by granting or rejecting a marketing authorisation.
If, after the assessment of the response, a positive opinion is reached on the benefit/risk balance, HALMED will issue a decision on granting the marketing authorisation with the approved SmPC, PL and labelling, and medicinal product may be placed on the Croatian market.
In addition to the decision on granting marketing authorisation, HALMED may request from the marketing authorisation holder measures that he is obliged to carry out after obtaining the marketing authorisation (Follow-up measure/FUM, or Post-authorisation measures/PAM). Follow-up measures after granting a marketing authorisation should not be a condition for placing the medicinal product on the market, nor should the fulfilling of these measures affect the product's benefit/risk balance. Only those data not available to the applicant during the marketing authorisation procedure and not critical for reaching the final opinion on the quality, safety and efficacy assessment may be requested.
If, after the assessment of the response, an opinion is reached that the benefit/risk balance is unfavourable and the approval has to be rejected, the application for granting a marketing authorisation has to be discussed again at the Committee. If the Committee confirms the proposed opinion on the rejection, HALMED issues a decision on the rejection of the marketing authorisation, informing the applicant of the grounds for the rejection.
Medicinal Products Database
Information on the authorised medicinal products, including the approved SmPCs, PLs and the public assessment reports (published for medicinal products for which the applications for granting a marketing authorisation were submitted after Croatia's accession to the EU) are available on the HALMEDˈs website in Medicinal Products Database.
The public assessment report is a summary of the detailed assessment reports on the dossier, which provides usable and transparent information adapted to the public, not including confidential information.
Variations and renewals
After obtaining a marketing authorisation, the marketing authorisation holder shall throughout the medicinal product life cycle, notify/submit to the HALMED all variations to the initially approved medicinal product dossier, product information and to the terms of the granted marketing authorisation, according to the HALMEDˈs instructions on Variations.
Five years after the marketing authorisation has been granted, the benefit/risk balance of the authorised medicinal product is once again re-evaluated in the renewal procedure. The application for the renewal of marketing authorisation has to be submitted by the marketing authorisation holder, following the instruction on Renewal of Marketing Authorisation. Based on the outcome of the re-evaluation, HALMED may renew the marketing authorisation for an unlimited period or, on justified grounds relating to pharmacovigilance, request additional five-years renewal for the medicinal product concerned.