Procedure for Granting Marketing Authorisation
Only those medicinal products 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.
HALMED grants a marketing authorisation for medicinal products authorised via national procedure and authorised via common European procedures: mutual recognition procedure (MRP) and decentralised procedure (DCP), whereas the European Commission grants marketing authorisations for centrally authorised products.
Marketing authorisations may be granted only for those medicinal products having an adequate quality and proved by scientific assessment of the product's documentation and having a positive benefits/risks ratio for use.
The scientific assessment is based on in advance defined criteria and established standards found in Croatian and European regulations and guidelines on medicines and their newest scientific findings.
Four marketing authorisation procedures for medicinal products:
There are four marketing authorisation procedures for medicinal products in the European Union regulatory environment:
- Centralised procedure,
- Decentralised procedure,
- Mutual recognition procedure and
- National procedure.
The following sections describe in details these procedures and provide instructions for submitting respective applications.
Centralised procedure (CP)
The documentation for centrally authorised medicinal products is scientifically assessed by the European Medicines Agency (EMA) and the marketing authorisation valid in all EU Member States is granted by the European Commission. Experts from all EU Member States including Croatia participate in quality, safety and efficacy assessment of every medicinal product.
This procedure is mandatory for medicinal products for HIV/AIDS, cancer, diabetes, neurodegenerative disorders, autoimmune disorders and other immunologic dysfunctions and viral diseases; 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. Also, the centralised procedure is possible, but not mandatory for all medicinal products with a significant therapeutic, scientific or technical innovation or the granting of their marketing authorisation is in the EU public health interest and for generics of centrally authorised medicinal products.
With the accession date of the Republic Croatia to the EU, all decisions for granting marketing authorisations for medicinal products based on the CP in the EU came also into effect in the Republic of Croatia.
More information on centrally authorised medicinal products and instructions how to access their relevant data are available in the Find medicine Section of the EMA webpages, or in the HALMED Medicines Database accessible under the link Medicinal products/HALMED data base.
Submission of an application for initiating a procedure
For the centralised procedure, the application and documentation are submitted to the EMA and more information on the centralised procedure, application procedure and progress is available on the EMA webpages, or here.
Mutual recognition procedure (MRP) and decentralised procedure (DCP)
MRP and/or DCP procedures are based on mutual recognition and recognition of the scientific assessment one of the EU member states, with the aim to grant marketing authorisations in all other member states where the same application has been submitted. The Republic of Croatia may participate in these procedures as a reference member state (RMS) that is leading the documentation assessment process or concerned member state (CMS) in the procedure. The medicinal product authorised in either of these two procedures may be on the Croatian market and on the market of more EU member states, depending on the number of member states participating in the procedure.
The decentralised procedure (DCP) for granting a marketing authorisation means that the marketing authorisation procedure starts at the same time in the reference member state and other EU member states participating in the procedure. It is mandatory for those medicinal products that fall outside of the scope of the centralised procedure, products that have not been previously granted marketing authorisations in the EU and products that will be on the market of more than one EU member state. It is about the procedure that is initiated if the product has not been previously authorised in any member state and the marketing authorisation holder wishes to place it on the market of two or more member states. In this case, the reference member state is assessing the product documentation for the first time with active participation of all member states concerned.
On the other side, the mutual recognition procedure (MRP) for granting a marketing authorisation starts after medicinal product has been authorised in the reference member state. According to marketing authorisation holder's choice, other EU member states may take part in the procedure. It is obligatory for all medicinal products that fall outside the scope of the CP or DCP and that will be on the market of more than one EU member state. The reference member state, where the product has been authorised via national procedure is forwarding its assessment report to other member states in the procedure. Also, like in the DCP procedure, after the completion of the procedure, all documents are harmonised (Summary of Product Characteristics, Package leaflet and Labelling) and the national marketing authorisation is valid for the member state territory.
More information on MRP and DCP procedures are accessible on the webpages of the Co-ordination Group for Mutual recognition and Decentralised Procedure (CMDh), or here.
In the MRP/DCP procedures section of its webpages, HALMED has made publically available the procedure for initiating a MRP/DCP procedure, including the explication how the procedure is initiated in the case where the Republic of Croatia acts as a reference member stats (RMS), what information should be included in the application form for granting a marketing authorisation and specific requirements for the Republic of Croatia in MRP/DCP procedures are described in more details.
National procedure (NP)
The last, fourth procedure for granting a marketing authorisation in the EU is the national procedure, that is being carried out when the applicant wishes to market the product in only one member state and the marketing authorisation is granted nationally and valid only on this country's territory.
Submission of applications for initiating MRP/DCP or national procedures in the Republic of Croatia:
- The procedure for submitting applications for granting a marketing authorisation in the Republic of Croatia is set out in the Medicinal Products act (Official Gazette, No 76/13 and 90/14) and Ordinance for granting marketing authorisations for medicinal products (Official Gazette No 83/13).
- The application for granting a marketing authorisation may be submitted to HALMED by a natural or legal person with the seat in the European Union (hereinafter: applicant).
Medicinal product documentation:
In addition to the application, the applicant should attach the medicinal product documentation that should be prepared in the Common Technical Document (CTD) form.
The essential parts of the CTD are the following:
- Module 1: Administrative data and product information
- Module 2: Documentation summaries
- Module 3: Quality
- Module 4: Reports on non-clinical trials
- Module 5: Reports on clinical trials
The structure of individual modules is described in Annex I to this Ordinance.
The documentation content may vary depending on the group that the product is belonging to and the chosen legal base for granting a marketing authorisation.
The medicinal product documentation may be in electronic (eCTD or NeeS) or paper form.
The medicinal product documentation is submitted in Croatian or English, except for the documentation stipulated by the Ordinance to be submitted in Croatian and attached as a copy, except for those documentation parts, stipulated by the Ordinance to be submitted in original, or copy certified by a notary.
In the Useful notes for applicant - documentation Section of its webpages, HALMED has made publically available Instructions for applicants with regard to preparation and submission of electronic and/or paper documentation.
The entire electronic documentation may be submitted via CESP or mail/courier on CD or DVD to the following address:
Agency for Medicinal Products and Medical devices (HALMED)
Ksaverska cesta 4
10 000 Zagreb
The paper documentation may be sent to this address, where the applicant is obliged to submit Modules 1, 2, 3, 4 and 5 in paper form. In addition, Modules 4 and 5 should be also in an electronic form.
In addition to the documentation, the marketing authorisation holder is obliged to submit the following documents:
Documents that should be submitted in the original or in a certified copy:
- Application for granting a marketing authorisation is submitted in the original, in Croatian, separately for every pharmaceutical form and strength, signed by the applicant's responsible person. The cover letter form for application for granting a marketing authorisation is available here.
- Application form is submitted in original, separately for every pharmaceutical form and strength, and signed by applicant's responsible person. It is completed in Croatian or English language. The application form for granting a marketing authorisation is available in the Forms section or under the following link: Application forms for granting/renewal/variation of the marketing authorisation for medicinal products in the Republic of Croatia.
- Written authorisations:
a) written authorisation by which the applicant's responsible person authorises a person for submitting applications, signing of the application form and contact on behalf and for the account of the applicant during the marketing authorisation procedure
b) written authorisation of the future marketing authorisation holder's responsible person, authorising the applicant to submit applications on his behalf, if the future marketing authorisation holder is not at the same time the applicant
c) written authorisation of the applicant's responsible person by which he authorises a person for submitting applications, signing of the application form and contact on behalf and for the account of the applicant after granting a marketing authorisation.
If the responsible person for submitting applications, signing of application forms and contact on behalf and for the account of the applicant during and after the marketing authorisation procedure is not employed by the applicant, the following authorisation should be attached:
- written authorisation of the legal entity's responsible person whose, authorised person is employed by the legal entity (employer's authorisation for employee to perform tasks on behalf of another legal entity)
Documents to be submitted in electronic form:
- Proof of the legal entity's seat, if the future marketing authorisation holder is a natural or legal person than the applicant, proof that the seat of the future marketing authorisation holder is in the EU, valid no longer than six months from the submission date
- Written statement of the marketing authorisation holder not having seat in the Republic of Croatia about the appointment of a local representative with the seat in the Republic of Croatia with his contacts
- Contract between the manufacturer(s) responsible for batch release and future marketing authorisation holder or applicant, if the manufacturer and future marketing authorisation holder or applicant are not the same person
- Proof that the future marketing authorisation holder has by the Agency authorised qualified person for pharmacovigilance with residence in the Republic of Croatia, or proof on submitted application to the Agency for approval of the qualified person for pharmacovigilance with residence in the Republic of Croatia
- Proof of the paid marketing authorisation procedure
Marketing authorisation process at HALMED
After receiving applications, HALMED begins with application validation where HALMED's regulatory experts review administrative data, verify their compliance with current regulations and further assess whether the submitted application is complete and in the current format according to the proposed legal base and product group.
During the validation process, the following aspects are being reviewed:
- the completeness of the documentation in general, completeness of attached forms and other documents,
- whether requested documents are submitted in adequate format,
- compliance of submitted documentation with the proposed legal base according to national and EU regulations and guidelines,
- whether all manufacturing sites have an adequate manufacturing license,
For all identified deficiencies, the applicant will be sent a Notice on invalid application with a deadline for completing the documentation.
After the application has been assessed as valid, the application is forwarded to the relevant co-ordination of the Regulatory affairs Department (national or MRP/DCP co-ordination), depending of the type of application. Regulatory experts in co-ordinations follow and co-ordinate the circulation of dossiers until the issuing of marketing authorisations.
After the application has been successfully validated, co-ordinators forward the application to the assessment procedure. The documentation assessment represents a critical overview on submitted data with regard to current regulations and guidelines in the Republic of Croatia and European Union and with regard to the newest scientific and technical achievements in research, development, manufacturing, quality control, safety and efficacy testing of medicines.
Quality assessors review the pharmaceutical, chemical and biological documentation on pharmaceutical-chemical development, manufacturing and quality control.
Non-clinical and clinical assessors review the documentation on non-clinical investigations in animals and clinical investigations in humans carried out during the medicinal product development phase in order to prove the safety and efficacy.
The quality assessment and non-clinical and clinical assessment are carried out in the Department for quality, safety and efficacy assessment.
Assessors in the Department for pharmacovigilance and rational pharmacotherapy review the documentation on the safe use, i.e. documentation on reported adverse reactions and risk management plan.
Assessors in the Department for regulatory affairs review results of package leaflet readability testing.
Allocated assessors write a detailed report on the documentation assessment. It is an internal document of the Agency, where information on the content review of every documentation part is documented with a critical overview on the essential data for adopting an opinion. Also, questions that need to be addressed to the applicant are indicated where necessary.
Questions addressed to the applicant are divided in questions related to potential human health risks (major deficiencies) and questions needing further clarification (minor deficiencies).
If the applicant has not provided satisfying answers to questions on the potential risk for public health, this represents an obstacle to granting a marketing authorisation.
During the documentation assessment procedure it is possible to request samples and documentation for laboratory testing depending on the decision and scope defined by the Head of the Department for assessment in agreement with the Head of the OMCL Division. Testing results from the assessment procedure and eventual comments regarding these results and analytical procedure are part of the medicinal product's quality assessment.
In addition, every assessment report is reviewed, revised by the HALMED's most experienced assessors in certain areas, who present the final opinion and co-sign the assessment report. In the case of very complex issues, the dossier is discussed at the internal assessors working groups to ensure consistency of decisions and opinions and to ensure an identical interpretation of regulations and guidelines by all assessors.
If additional specific knowledge is needed for the assessment, the Agency may appoint external experts strictly specialised in certain areas.
The review of proposals for the summary of product characteristics, package leaflet and labelling is an integral part of the documentation assessment. The product information must comply with the submitted documentation and current guidelines stipulating its format and content.
Committee for medicinal products
After completing the assessment, the assessor informs the concerned co-ordination of the Department for regulatory affairs. After the co-ordinator has collected all reports in a single marketing authorisation procedure, the dossier is forwarded to the Committee for medicinal products composed of HALMED staff members and depending on the occasion, from external experts. For the assessment of the full non-clinical and clinical documentation, or all applications encompassing proper non-clinical and clinical trials, or those published in the literature, in addition to HALMED's assessors, external experts mostly doctors specialists in certain therapeutic areas, having specific practical knowledge and experience in the treatment of indications concerned are appointed, thus contributing to the quality of assessment. Final conclusions and questions are defined at meetings of the Committee as well as questions to be forwarded to applicants. Meetings of the Committee are held every week in permanent assembly and depending on the need in extended assembly. The schedule of meetings is available here. Minutes are being taken at meetings and these minutes are endorsed within 2 days after the meeting and may be found here.
Conclusions on deficiencies
After the meeting and endorsement of minutes, according to the Committee's conclusions, individual co-ordinations prepare the Conclusion on deficiencies in the documentation and an official letter to the applicant containing questions and comments with regard to the submitted documentation and request for additional documentation, if the submitted data is not sufficient for a positive quality, safety and efficacy assessment of the medicinal product.
Finalisation of procedures
When the requested additional documentation has been submitted and assessed by reviewers who previously asked questions, the procedure is ended up in granting or rejecting a marketing authorisation.
Authorised texts of summary of product characteristics, package leaflet and labelling are issued attached to the marketing authorisation and the concerned medicinal product may be placed on the Croatian market.
In addition to the marketing authorisation, it is possible to propose measures that the applicant is obliged to carry out (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 influence the product's benefit/risk ratio. Only those data not available to the applicant during the marketing authorisation procedure and not crucial for concluding the quality, safety and efficacy assessment may be requested. If after the submission of additional data the opinion is to reject the granting of a marketing authorisation, the dossier is discussed again at the Committee for Medicinal Products.
After granting a marketing authorisation, basic information on the authorised medicine, including the approved summary of product characteristics and package leaflet and the public assessment report for medicines whose applications were submitted after Croatia's accession to the EU (1st July 2013) are being published in the Medicinal Products Database of the HALMED webpages and are publically available. The public assessment report on the medicinal product's documentation is a summary of complete detailed product reports not containing commercially sensitive details.
Public Assessment Report is a summary of complete detailed asssessment reports which does not contain confidential data.
Variations and renewals
After granting a marketing authorisation, the marketing authorisation holder is obliged to report to HALMED all variations to the previously authorised documentation throughout the medicinal product life cycle. Variations may be administrative variations (i.e. change of the manufacturer's address), change in the documentation on quality (i.e. change in the manufacturing procedure, quality control methods), change in safety information resulting through new post-authorisation studies (i.e. including of new side effects in the package leaflet) and changes in indications (adding or omitting certain indications). The marketing authorisation holder is required to follow the newest scientific and technological advances in the field of development, testing and regulations of medicines and implement them through variations of the medicinal product that is on the market.
Five years after the first marketing authorisation, the benefit/risk ratio of the authorised medicinal product is once again reviewed in the renewal process. Depending on the result of the review, the marketing authorisation may be renewed for an unlimited period or the marketing authorisation is to be renewed after the following five years.