Marketing, Manufacturing, Packaging & Labeling, Advertising
An insight into marketing, manufacturing, packaging & labeling, and advertising in Croatia. Prepared in association with Danijel Pribanić, a leading global law firm, this is an extract from The Pharma Legal Handbook: Croatia, available to purchase here for USD 99.
1. What is the authorization process for the marketing of new drugs, biologics, medical devices, over-the-counter medications, and other medicinal products?
B) MEDICINAL PRODUCTS
Only those medicinal products having a marketing authorisation granted by the Agency for Medicinal Products and Medical Devices (HALMED – abbrevaiation of the Croatian name of this agency is commonly used) or the European Commission (EC) may be placed on the market in 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.
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 detail these procedures and provides instructions for submitting respective motions.
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 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 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 a Motion for Initiating a Procedure
For the centralised procedure, the motion and documentation are submitted to the EMA and more information on the centralised procedure, motion 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 motion has been submitted. 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 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 asseses 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 foward 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 on official site of the Agency.
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 Croatia acts as a reference member stats (RMS), what information should be included in the motion form for granting a marketing authorisation and specific requirements 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 motions for initiating MRP/DCP or national procedures in Croatia:
The procedure for submitting motions for granting a marketing authorisation in Croatia is set out in the Medicinal Products Act and Ordinance for granting marketing authorisations for medicinal products.
Motion for granting a marketing authorisation may be submitted to HALMED by a private individual or business entity with the seat in the European Union (hereinafter: applicant).
Medicinal Product Documentation:
In addition to the motion, 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 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 in paper form.
The medicinal product documentation is submitted in Croatian or English, except for the documentation stipulated by the Ordinance for granting marketing authorisation 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
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:
- Motion for granting a marketing authorisation is submitted in the original, in Croatian, separately for every pharmaceutical and strength, signed by the applicant’s responsible person. The cover letter form for motion for granting a marketing authorisation is available on the official website of the Agency.
- Motion is submitted in original, separately for every pharmaceutical and strength, and signed by applicant’s responsible person. It is completed in Croatian or English language. The motion form for granting a marketing authorisation is available in the Forms section or under the following link: Motionforms for granting/renewal/variation of the marketing authorisation for medicinal products in Croatia.
- Written authorisations:
a) written authorisation by which the applicant’s responsible person authorises a person for submitting motions, signing of the motion 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 motions on his behalf, if the future marketing authorisation holder is not at the same time the applicant, and
c) written authorisation of the applicant’s responsible person by which he authorises a person for submitting motions, signing of the motion form and contact on behalf and for the account of the applicant after granting a marketing authorisation.
If the responsible person for submitting motions, signing of motion 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, 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) should be attached.
Documents to be submitted in electronic form:
- proof of the legal entity’s seat, if the future marketing authorisation holder is a private individual or business entity 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 Croatia about the appointment of a local representative with the seat in 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 Croatia, or proof on submitted motion to the Agency for approval of the qualified person for pharmacovigilance with residence in Croatia;
- proof of the paid marketing authorisation procedure;
- proof of the paid administrative fee in the amount of HRK 225 (approx. EUR 30) for every pharmaceutical and strength.
Marketing Authorisation Process at HALMED:
After receiving motions, HALMED begins with motion validation where HALMED’s regulatory experts review administrative data, verify their compliance with current regulations and further assess whether the submitted motion 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, etc.
For all identified deficiencies, the applicant will be sent a Notice on invalid motion with a deadline for completing the documentation.
After the motion has been assessed as valid, the motion is forwarded to the relevant co-ordination of the Regulatory affairs Department (national or MRP/DCP co-ordination), depending of the type of motion. Regulatory experts in co-ordinations follow and co-ordinate the circulation of casefiles until the issuing of marketing authorisations.
After the motion has been successfully validated, co-ordinators forward the motion to the assessment procedure. The documentation assessment represents a critical overview on submitted data with regard to current regulations and guidelines in 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 casefile 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 are an integral part of the documentation assessment. The product information has to 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 casefile 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 motions encompassing proper non-clinical and clinical trials, or those published in the literature, in addition to HALMED’s assessors, external experts mostly doctors who are 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 on the official website of the Agency.
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 ends 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 casefile 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 motions 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.
A) MEDICAL DEVICES
Authorization of medical devices is not necessary to market a medical device.
Medical devices may be made available on the market of Croatia only if they do not compromise the safety and health of patients, users and other persons and only if they have been properly manufactured, correctly installed, maintained and used in accordance with their intended purpose.
Medical devices must meet the essential requirements taking into account the intended use of a particular medical device.
Any manufacturer of a medical device who has his registered place of business in Croatia and any authorised representative of the manufacturer of the medical device with its registered place of business in Croatia who place a medical device classified as Class I on the market has to inform the Agency and thereby apply for the registration of the medical device concerned in the register of the medical devices within the time period not exceeding 15 days from the day on which the medical advice was first placed on the market.
2. What is the authorization process for the marketing of generic versions of these products?
The authorization process for the marketing of generic version of products is regulated by Medicinal Products Act and Ordinance on Granting Marketing Authorisations for Medicinal Products.
Without prejudice to the regulations relating to the protection of industrial and intellectual property, the applicant for the marketing authorization is not required to provide the results of pharmaceutical and pre-clinical tests and of clinical trials, if he can demonstrate that the medicinal product is a generic which is or has been authorised for not less than eight years in an EU Member State based on the centralised marketing authorisation procedure.
The marketing authorisation applicant cannot place on the market the generic medicinal product until 10 years have elapsed from the initial authorisation of the reference product.
The 10-year period may be extended to a maximum of 11 years if, during the first eight years of the ten-year period the marketing authorisation holder obtains an authorisation for one or more new therapeutic indications which, during the scientific evaluation prior to their authorisation, are held to bring a significant clinical benefit in comparison with existing therapies.
The referred reference medicinal product means the one which is or has been authorised in an EU Member State in accordance with Directive 2001/83/EC or provisions of Regulation (EC) No 726/2004, based on fully documented quality, efficacy and safety of the medicinal product.
Generic medicinal product means a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.
Diifferent salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of various salts, esters or derivatives of an authorised active substance has to be supplied by the applicant.
Various immediate-release oral pharmaceuticals are considered to be one and the same pharmaceutical.
Bioavailability studies need not be submitted by the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the guidelines of the European Commission and of the EMA. For the purpose of submitting motions and placing generic medicinal products on the market, the protection periods is calculated as of the date of the initial authorisation within the global authorization.
The protection periods (10 or 11 years) also applies to the reference medicinal products with a view to the submission of motions in accordance Medicinal Products Act.
Alongside the motion for the granting of marketing authorisation for a generic medicinal product, the applicant is obliged to append Modules that contain the data prescribed by the Medicinal Products Act and Ordinance on Granting Marketing Authorisations for Medicinal Products, and data on bioavailability and bioequivalence with the reference medicinal product, in line with the guidelines of the European Union.
The applicant requesting grant of marketing authorisation for a generic medicinal product is obliged to prove that the motion and casefiles are in compliance with the Medicinal Products Act.
The proposed Summary of product characteristics of the medicinal product and package leaflets for Croatia is aligned with the Summary of product characteristics of the medicinal product and package leaflets of the reference medicinal product authorised in Croatia or a European Union Member State, as listed in the motion form for the granting of authorisation.
The appended expert report/summary on preclinical and clinical documentation in Module 2 is particularly directed at:
- an assessment of the foundedness of claims of the equivalence of the medicinal product with the reference medicinal product;
- an assessment of the acceptability of impurities present in the active substance(s) and impurities in the medicinal product (including degradation products arising during storage) fo medicinal products under preparation;
- an assessment of the conducted bioequivalence testing or substantiation as to why such testing was not conducted in accordance with the valid guidelines of the European Union for testing bioavailability and bioequivalence;
- a new review of the published literature pertaining to the active substance and the submitted motion (for this purpose, articles from peer-reviewed scientific journals may be accepted), and
- for each claim in the Summary of product characteristics of the medicinal product not ensuing from the properties of the medicinal product and/or its therapeutic groups, a critical overview should be provided and supported by the published literature and/or additional testing.
The different salts, esters, ethers isomers, mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, alongside the motion for the granting of marketing authorisation for a generic medicinal product, additional information providing proof of the safety and/or efficacy of various salts, esters or derivatives of an authorised active substance are supplied by the applicant.
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.
3. What are the typical fees for marketing approval?
A) MEDICINAL PRODUCTS
An administrative fee of HRK 225 (approx. EUR 30.00) has to be paid for each pharmaceutical and strength of the drug.
B) MEDICAL DEVICES
Specific authorization for manufacture of medical devices and marketing authorization of a medical device is not required.
4. What is the period of authorization and the renewal process?
The Agency grants marketing authorisations for medicinal products for the period of five years.
Not later than nine months before the marketing authorisation ceases to be valid, motion for its renewal may be submitted to the Agency. The Agency may renew the marketing authorisation for a further period of next five years subject to reassessment of the product‘s risk-benefit balance.
In addition to the motion for renewal of the marketing authorisation, the marketing authorisation holder provides the Agency with a consolidated version of the file in respect of quality, safety and efficacy, including the evaluation of data contained in suspected adverse reactions reports and in the periodic safety update reports submitted in accordance with pharmacovigilance provisions of Medicinal products, and information on all variations introduced since the marketing authorisation was granted till the date of motion for its renewal.
Once renewed, the marketing authorisation is valid for an unlimited period, unless the Agency decides, on justified grounds relating to pharmacovigilance, including exposure of an insufficient number of patients to the medicinal product concerned, to proceed with one additional five-year renewal.
The written request of the applicant is submitted separately for each pharmaceutical and strength of the medicinal product.
The marketing authorisation renewal request for a medicinal product contains:
- name of the medicinal product;
- active substance;
- pharmaceutical and strength;
- pharmacotherapeutic group according to the ATK classification;
- authorisation number;
- number of the MRP/DCP procedure, if applicable;
- data on the applicant (name and seat);
- data on the form of a casefile (eCTD, NeeS, hardcopy);
- date and signature of responsible person in the applicant, and
- list of documentation on the medicinal product enclosed with the motion.
Alongside the motion for renewal of the marketing authorisation, the authorization holder is obliged to submit the documentation containing the data and documents pursuant to Ordinance on Granting Marketing Authorisations for Medicinal Products.
5. What are the requirements, if any, for post-approval pharmacovigilance?
Requirements for post-approval pharmacovigilance are regulated by the Medicinal Products Act and Ordinance on Pharmacovigilance.
Upon request by the Agency, particularly in the context of pharmacovigilance, the marketing authorisation holder submits the data relating to the volume of sales of the medicinal product and data relating to the volume of prescriptions.
The Agency may lay down that medicinal products approved for placement on the market be additionally monitored due to their safety profile. These medicinal products bear a special label.
Any healthcare professional who comes in contact with patients/users of a medicinal product, any manufacturer of a medicinal product and a marketing authorisation holder, holder of an authorisation for parallel import and wholesaler has to notify the Agency in writing about any suspected adverse reactions, in particular about serious and unexpected adverse reactions, while in the case of vaccines they have to also notify the Croatian National Institute of Public Health.
A healthcare professional has to report serious adverse reactions to the Agency within 30 days after their knowledge and later as necessary by filing subsequent reports. Serious adverse reactions with a fatal outcome has to be forthwith reported to the Agency in writing or by phone, subject to the subsequent written notification.
A healthcare professional who participates in a clinical trial as investigator has to forthwith report all serious adverse events to a clinical trial sponsor, except if he is not required to do this by the trial protocol and the investigator‘s brochure.
The marketing authorisation holder operates a pharmacovigilance system for the fulfilment of his pharmacovigilance tasks provided for by the provisions of Medicinal Products Act and the ensuing Ordinance on Pharmacovigilance.
The marketing authorisation holder has to, by means of the pharmacovigilance system, evaluate all information scientifically, consider options for risk minimisation and prevention and take regulatory action as necessary.
The marketing authorisation holder performs a regular audit of the pharmacovigilance system. He places a note concerning the main findings of the audit on the pharmacovigilance system master file (PSMF) and, based on the audit findings, ensure that an appropriate corrective action plan is prepared and implemented. Once the corrective actions have been fully implemented, the authorisation holder may remove the above referred note.
As part of the pharmacovigilance system, the marketing authorisation holder has to:
- have permanently and continuously at his disposal:
– an appropriately qualified person responsible for pharmacovigilance in the European Union and
– an appropriately qualified person responsible for pharmacovigilance in Croatia;
- maintain and make available on Agency‘s request a pharmacovigilance system master file;
- operate a risk management system for each authorised medicinal product;
- monitor the outcome of risk minimisation measures which are contained in the risk management plan or which are laid down as conditions pursuant to Medicinal Products Act, and
- update the risk management system and monitor pharmacovigilance data to determine whether there are new risks or whether risks have changed or whether there are changes to the benefit-risk balance of medicinal products.
Tasks of the person responsible for pharmacovigilance in the European Union and in Croatia, referred above may be performed by a single person.
The marketing authorisation holder has to:
- keep records of all suspected adverse reactions in Croatia, other Member States of the European Union or third countries reported to him, either spontaneously by patients/users of the medicinal product or a healthcare professional or reported during the post-authorisation study, and
- make available the above-mentioned data at one location in the European Union.
Marketing authorisation holders has to submit electronically to the Eudravigilance database:
- information on all non-serious suspected adverse reactions that occur in Croatia within 90 days following the day on which the marketing authorisation holder concerned gained knowledge of the event;
- information on all serious suspected adverse reactions that occur in Croatia within 15 days following the day on which the marketing authorisation holder concerned gained knowledge of the event;
- information on all non-serious suspected adverse reactions that occur in the Member States of the European union, within 90 days following the day on which the marketing authorization holder concerned gained knowledge of the event;
- any information on all serious suspected adverse reactions that occur in the Member States of the European union within 15 days following the day on which the marketing authorization holder concerned gained knowledge of the event, and
- information on all serious suspected adverse reactions that occur in the third countries following the day on which the marketing authorisation holder concerned gained knowledge of the event.
Marketing authorisation holders have to establish procedures in order to obtain accurate and verifiable data for the scientific evaluation of suspected adverse reaction reports. They also have to collect follow-up information on these reports and submit the updates to the Eudravigilance database.
Marketing authorisation holders have to collaborate with the Agency and the EMA in the detection of duplicates of suspected adverse reaction reports.
Marketing authorisation holders submits electronically all suspected adverse reactions regulated by the Medicinal Products Act to the Agency until the functional system for their submission to the Eudravigilance database has been established.
The Agency submits all suspected adverse reactions reports received to the Eudravigilance database in accordance with above-mentioned timeframes (15 or 90 days).
The authorisation holder has to submit to the Pharmacovigilance Risk Assessment Committee a draft protocol of the study, which is to be conducted pursuant to the obligations stipulated by provisions of Medicinal Products Act. Except in the case when the authorisation holder submits to the Agency a draft protocol of the study, which is to be conducted only in Croatia, subject to the request by the Agency.
In that case 30 days befre the submission of the draft, the Agency has to:
- provide a written notification of approval for the draft protocol, or
- provide a written notification about the shortfalls when:
– it considers that the conduct of the study promotes the use of a medicinal product,
– it considers that the design of the study does not fulfil the study objectives, or
- provide a letter notifying the marketing authorisation holder that the study is a clinical trial falling under the scope of Directive 2001/20/EC.
The study for which the authorization holder has to submit draft protocol to the Pharmacovigilance Rish Assessment Committe may commence in Croatia subject to a written endorsement by the PRAC and following the submission of the approved draft study protocol to the Agency by the authorisation holder.
The study for which the authorization holder has to submit a draft protocol of the study to the Agency, the study may commence following the written approval by the Agency.
After a study for which the authorization holder submits draft protocol to the Pharmacovigilance Rish Assessment Committee has commenced, the marketing authorisation holder has to submit to the PRAC and obtain their written endorsement for any substantial amendments to the protocol, before their implementation.
The marketing authorisation holder notifies the Agency of any approved substantial amendments to the study protocol prior to their implementation.
Following the commencement of the study for which the authorization holder submits a draft protocol of the study to the Agency, the marketing authorisation holder has to submit to the Agency any substantial amendments to the draft study protocol and obtain their written approval prior to their implementation.
Upon the completion of the study for which the authorization holder submits draft protocol to the Pharmacovigilance Rish Assessment Committee, the marketing authorisation holder has to submit, within 12 months from the end of data collection, a final study report and a summary of the study results to the PRAC, unless a written postponement or a written waiver has been granted by the PRAC.
Upon the completion of the study for which the authorization holder submits a draft protocol of the study to the Agency, the marketing authorisation holder has to submit, within 12 months from the end of data collection, a final study report and a summary of the study results to the Agency, unless a written postponement or a written waiver has been granted by the Agency.
If the results of both studies have any impact on the marketing authorisation, the marketing authorisation holder has to submit a motion to vary the marketing authorisation.
The marketing authorisation holder submits periodic safety update reports to the Agency immediately upon request or in accordance with the following:
- where a medicinal product has not yet been placed on the market, at least every 6 months following authorisation and until the placing on the market, and
- where a medicinal product has been placed on the market, at least every 6 months during the first 2 years following the initial placing on the market, once a year for the following two years and at three-yearly intervals thereafter.
The healthcare professional, the applicant for marketing authorizations, marketing authorization holder, authorization holder for parallel imports, importer, and wholesale report the therapeutic failure of the medicinal product in accordance with the Guideline on good pharmacovigilance practices (GVP) Module VI – Management and reporting of adverse reactions to medicinal products.
The respective pharmacovigilance systems of the Agency and marketing authorization holders have defined algorithms for the assessment of the causal relationship between an adverse event and the medicinal product in the case of an adverse reaction to the medicinal product, in accordance with the Guideline on good pharmacovigilance practices (GVP) Module VI – Management and reporting of adverse reactions to medicinal products.
6. Are foreign marketing authorizations recognized?
The Agency grants marketing authorisations for medicinal products through the national procedure, the mutual recognition procedure and the decentralised procedure by means of the decision which marks the completion of the authorisation procedure carried out in accordance with Medicinal Products Act and ensuing regulations. Croatia can be either the reference state or the concerned state in the mutual recognition procedure and decentralised procedure.
European Commission grants marketing authorisations based on the centralized procedure in accordance with the provisions of the Regulation (EC) No 726/2004.
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.
Please see chapter 3 question 1 for more information on marketing authorization procedures.
7. Are parallel imports of medicines or devices allowed?
Procedure of parallel import is regulated by Ordinance on Granting Authorisation for the Parallel Import of Medicinal Products (Official Gazette No. 122/14). Written request to the Agency is required for parallel import.
The procedure for granting the authorisation for parallel import is initiated with a written motion submitted to the Agency pursuant to the provisions of the Medicinal Products Act and Ordinance on Granting Authorisation for the Parallel Import of Medicinal Products.
The applicant is obliged to submit the motion for issuance of the authorisation for the parallel import of medicinal products in Croatia in the original, in Croatian. The motion is submitted separately for each pharmaceutical and strength of the medicinal product.
The motion for the issuance of authorisation for parallel import may be submitted by a wholesaler holding a permit for the wholesale of medicinal products issued by the Agency or competent body of another European Union Member State, and which is not in business relations with the marketing authorisation holder for the medicinal product that is the subject of the motion.
8. What are the restrictions on marketing practices such as gifts, sponsorships, consultancy agreements, travel and entertainment, or other incentives for healthcare organizations and individual medical practitioners?
A) MEDICINAL PRODUCTS
While advertising the medicinal product, it is not permitted to stimulate the healthcare professional authorised to recommend, prescribe or dispense medicinal products to prescribe, dispense, procure or recommend medicinal products by providing rewards in money, gifts or enabling any other material gain, or promise of benefit or reward, unless such are small and of symbolic value (to HRK 70, approx. EUR 9.00) and are related to the practice the healthcare professional performs. Healthcare professionals may not request nor accept stimulations for the prescription, dispensing, sale or consumption of medicinal products. Above-mentioned does not apply to existing measures or trade practices that pertain to the determination of the price of the medicinal product, accompanying margin and discounts.
Professional and scientific meetings and lectures organised or financed by manufacturers, marketing authorisation holders and importers, or wholesale distributers of medicinal products, have to be scientifically founded and educational. The content of such meetings primarily has a professional character. All other content of the meetings have to be auxiliary in relation to the main purpose and content of the meeting. Meeting has to be intended exclusively for healthcare professionals. During the organisation of meetings, it is permitted to cover the costs of the registration fee, travel, accommodation and food for healthcare professionals that participate in the meeting, to the level of the actual value of the said costs. It is not permitted to cover the said costs of persons who are not participants of the meeting (e.g. persons accompanying the healthcare professional). In selecting the venue for the meeting, the manufacturers, marketing authorisation holders and importers, or wholesale distributers of medicinal products, are obliged to select an appropriate venue, with services of a primarily business and/or congress content.
The marketing authorisation holder may secure free trial samples of a medicinal product to a healthcare professional authorised to recommend, prescribe or dispense medicinal products, under the condition that it does not differ from the usual packaging, that it is the smallest packaging having marketing authorisation in Croatia and which is available on the market, and that the sample is clearly labelled with the words “free sample – not for sale”. In the storage and dispatch of the free samples, it is necessary to handle them in accordance with the good practice requirements in the wholesale trade of medicinal products. Free samples have to be equipped and include the package leaflet pursuant to the marketing authorisation. The healthcare professional may, upon written request and with the signature of receipt, receive a free sample of a medicinal product only once in the course of a year, and that in the amount of a maximum of two of the smallest original packages, and the marketing authorisation holder is obliged to keep a record thereof. The record states the name and surname of the healthcare professional, the name of the institution or private practice and the date the free sample was given to the healthcare professional, and information on the lot number and expiry period of the sample. Records have to be kept for a minimum of two years from the date the healthcare professional received the sample.
It is not permitted to perform advertising towards healthcare professionals by handing out trial samples of medicinal products containing narcotic drugs and psychotropic substances, pursuant to a special regulation governing the prohibition of drug abuse, nor medicinal products from the list of especially expensive medicines.
In the procedure of advertising the medicinal product towards healthcare professionals, the following is not permitted:
- convincing the healthcare professional to replace one medicinal product with another from the therapeutic group, without the existence of a clear medical indication to do so;
- making claims or conclusions on the efficacy of medicinal products in indications that are the subject of clinical trials in the country or abroad;
- making claims that a medicinal product has no adverse reactions and that it is not toxic or that there is no risk of forming an addiction, if such claims are not corroborated by evidence;
- indicating the summary of product characteristics of a medicinal product, significant information from the summary of product characteristics of the medicinal product or approved instructions for use, using a font size smaller than 3 mm;
- use of postcards or other forms of postal consignments whose content may be accessible and legible to other person other than healthcare professionals, and
- use of the telephone, fax, electronic mail and other electronic systems without the prior consent of the healthcare professional as the preferred form of advertising.
B) MEDICAL DEVICES
There are no specific requirements and restrictions on marketing practices of medical devices such as gifts, sponsorships, consultancy agreements, travel and entertainment or other incentives for healthcare organizations and individual medical practitioners.
9. How is the manufacturing of medicines and devices regulated and by which agencies?
A) MEDICINAL PRODUCTS
Primary legislation for the manufacturing approval and manufacture is the Medicinal Act and its regulations.
Private individuals or entities who manufacture medicinal product have to comply at least with the following requirements:
- given the scope and complexity of manufacture of a medicinal product or a group of medicinal products, they must have the adequate number of qualified persons in the field of in pharmacy, chemistry, biology, biochemistry, biotechnology, chemical technology, medicine, dental medicine, veterinary medicine or other corresponding professions;
- they must have employed a qualified person for the release of a medicinal product batch who should be permanently available;
- they must have employed key personnel for the manufacture, quality checks and distribution of medicinal products;
- they must have at their disposal suitable premises and equipment requisite for the manufacture, quality control, storage and delivery of medicinal products, and
- they must observe the principles and guidelines of Good Manufacturing Practice
Manufacture of medicinal products is regulated by the Agency.
B) MEDICAL DEVICES
Manufacture of medical devices does not require a specific authorization.
Private individual or legal entity with its registered place of business in Croatia who manufactures or makes a medical device, including the medical devices referred to in has to:
- ensure that the medical device that he manufactures has been designed and manufactured in
accordance with the requirements provided by Medical Devices Act;
- carry out the classification of the medical device according to the associated risk, draw up the relevant technical documentation and conduct or ensure the conduct of an applicable conformity assessment procedure for the medical device concerned;
- draw up the conformity declaration and affix the CE marking to the medical device in
- keep available the technical documentation and the conformity declaration for at least five years after the medical device has been placed on the market;
- ensure the procedures with the view to pertaining the conformity of the batch or serial;
- properly label and mark the medical device and supplement it with the instructions for use;
- undertake corrective actions where it can be assumed or where there is a reason to believe that the medical device which has been placed on the market does not comply with the provisions of Medical Devices Act,
The manufacturer of a medical device shall be insured against harmful effects which might occur by the use of the medical device.
The Agency makes a decision on the entry of a manufacturer of a medical device into the register of manufacturers.
10. Are local manufacturing requirements compatible with Good Manufacturing Practices (GMPs) as defined by the U.S. Food & Drug Administration and/or the European Medicines Agency?
Manufacturing requirements of the European Medicines Agency are fully applicable in Croatia.
11. What is the inspection regime for manufacturing facilities?
A) MEDICINAL PRODUCTS
The supervision of the implementation of the provisions of Medicinal Products Act in respect of production and manufacture is carried out by the pharmaceutical inspectorate of the Ministry of Health.
The supervision of the implementation of the provisions of Medicinal Products Act in regard of the production of medicinal products is performed by the Agency.
B) MEDICAL DEVICES
Supervision of the implementation of provisions of Medical Devices Act and the bylaws adopted on the basis of this Act has to be carried out by pharmaceutical inspectors of the Ministry of Health.
The Agency can remove the manufacturer from the register of manufacturers of medical devices.
12. Are manufacturing facilities open for inspection by foreign inspectors or third-party inspectors as authorized by the FDA/EMA?
The Medicinal products Act and Medical Devices Act regulate only inspection by the pharmaceutical inspectorate of the Ministry and supervision performed by the Agency. Foreign inspector are not empowered to exercise supervision in Croatia.
13. What are the requirements for storage, packaging, and handling of medicines and devices and their constituent components?
A) MEDICINAL PRODUCTS
Wholesaler distributors are required to provide suitable premises, installations and equipment so as to ensure the performance of wholesale distribution of medicinal products; such premises should be located, designed, constructed, adapted and maintained in such a way as to enable the undisturbed flow of operation and safe and compliant placement, holding and distribution of medicinal products.
Working and storage areas have to be clean, dry and maintained within acceptable temperature limits stipulated for the storage of medicinal products.
The equipping and size of storage areas have to be suitable for the type of medicinal products and the scope of envisaged distribution.
Where premises are not directly operated by the wholesale distributor, a contract should be in place with authorised wholesale distributors for medicinal products that have their own premises.
Medicinal products have to be stored in segregated areas which are clearly marked and have access restricted to authorised personnel only.
Wholesale distributors have to take security measures to prevent unauthorised access to to all areas. Visitors have to be accompanied by authorised persons.
There has to be adequate separation of the receipt and dispatch area from the storage area, and both medicinal products and investigational medicinal products have to be protected from prevailing weather conditions.
Medicinal products with special storage conditions (e.g. medicinal products containing narcotics and psychotropic substances of the types II and III, radiopharmaceuticals, dangerous substances, medicinal products requiring special safety measures due to the risk from fire and/or explosion, such as medical gases, combustibles and flammables) should be segregated and stored in accordance with prescribed conditions. Storage methods should be defined by written procedures and harmonised with special regulations.
The distribution of radioactive medicinal products may be performed by wholesale distributors that meet the requirements laid down by regulations on protection against ionizing radiation.
Medicinal products pending a decision as to their use or products that have been recalled due to damaged integrity of the packaging, damaged packaging, or those suspected of contamination or being falsified, as well as returned medicinal products have to be segregated either physically or through an equivalent electronic system.
Any recalled medicinal products, medicinal products that may not be used pursuant to a decision (rejected medicinal products), whose shelf-life has expired and falsified medicinal products should be immediately physically segregated and stored in a dedicated area, so as not to be placed on shelves and sold by mistake or released to circulation.
Medicinal products received from third countries, which are not intended for the European Union market, but for the export into third countries, have to be stored in a physically segregated area.
In addition to storage areas, the wholesale distributors have to also provide auxiliary rooms, a toilet with entry area, and a wardrobe that has to be separated from the area in which medicinal products are kept.
Bringing, storing and consumption of food, drink, tobacco products or medicinal products for personal use should be prohibited in the area intended for the storage of medicinal products.
The wholesale distributor is required to provide suitable equipment and prescribe procedures to check the environment (temperature and moisture, light and cleanliness) where medicinal products are stored. A temperature mapping exercise should be carried out on the storage area under representative conditions.
All equipment used for the storage and distribution of medicinal products should be designed, located and maintained to a standard which suits its intended purpose. Planned maintenance should be in place for key equipment vital to the functionality of the operation.
Equipment repair, maintenance and calibration operations should be carried out in such a way that the integrity of the medicinal products is not compromised, and records should be kept thereof.
Premises, equipment and software used for wholesale distribution have to be adequately qualified and/or validated. The subject and scope of qualification and/or validation activities should be determined using a documented risk assessment approach/analysis.
When electronic records are used in the good practice in the wholesale distribution, protection from unauthorised access to the database has to be in place. Data should be secured by physical or electronic means and protected against accidental or unauthorised modifications, and checked for availability, durability and accuracy. Backup data should be stored at regular intervals, so that they are retained at a separate and secure location for a minimum period of five years.
Medicinal products have to be transported in such a way so that:
- their quality and identification is not lost;
- contamination is avoided;
- appropriate measures are taken against damage, spillage, breakage or theft;
- they are protected from adverse effects of heat, cold, exposure to light, moisture, etc.;
- they are protected from microorganisms or pest infestation, and
- temperature conditions are observed, as prescribed by the manufacturer or indicated on the outer packaging and monitored with calibrated equipment during transportation.
Risk assessment of delivery routes should be used.
If a deviation such as temperature excursion has occurred during transportation, this should be reported to the distributor and recipient of the affected medicinal products, and a procedure should be in place for investigating temperature excursions.
The wholesale distributor is responsible to ensure that vehicles and equipment used to distribute, store or handle medicinal products are suitable for their use and appropriately equipped to prevent exposure of the products to conditions that could affect their quality and packaging integrity.
For emergency deliveries outside normal business hours, persons should be designated, and prescribed procedures should be available.
Where transportation is outsourced by the wholesale distributor, the contract should encompass the requirements of Ordinance on Good Practice in the Distribution of Medicinal Products, on Issuing Authorisations for Wholesale Distribution of Medicinal Products, Registration for Brokering of Medicinal Products and on Issuing Certificates on Good Practice in Wholesale Distribution of Medicinal Products and transportation providers should be made aware by the wholesale distributor of the prescribed transport conditions applicable to the transportation of medicinal products.
Measures should be taken to minimise the duration of temporary storage while awaiting the next stage of the transportation route.
Medicinal products should be transported in containers that have no adverse effect on the quality of the products, and that offer adequate protection from external influences, including contamination. Containers should bear labels providing sufficient information on handling and storage requirements and precautions to ensure that the products, the contents of the containers and the source are properly handled at all times.
In relation to deliveries containing medicinal products requiring special conditions such as narcotics or psychotropic substances, the wholesale distributor should maintain a safe and secure supply chain for these products with an additional control system for delivery of these products. There has to be a protocol to address the occurrence of any theft. Medicinal products comprising highly active and radioactive materials have to be transported in safe, secure containers and vehicles intended for such purpose. For temperature-sensitive products, qualified equipment is used to ensure that correct transport conditions are maintained between the manufacturer, wholesale distributor and customer.
B) MEDICAL DEVICES
The premises have to be functionally connected to enable the undisturbed flow of operation and safe placement and keeping of medical devices and be equipped in such a way as to enable the establishment, maintenance and monitoring of the keeping conditions stipulated by the manufacturer.
The area for the receipt of medical devices has to be separate from the area for the dispatch and the area for the storage of medical devices.
The premises have to be constructed of solid materials and connected to the municipal infrastructure, with appropriate access for incoming and outgoing deliveries of medical devices that is protected from weather conditions. The walls and ceilings of the premises have to be such that enables cleaning and washing. The floors of wholesale premises have to be smooth and made in a way that enables cleaning, washing and, if necessary, disinfection.
All premises have to be ventilated, clean and dry. If natural air flow is insufficient, it is necessary to install effective artificial ventilation.
The premises and positioning of equipment has to enable the implementation of pest control measures, the appropriate cleaning and washing measures, measures against spillage and breakage, and against the effects of microorganisms and cross-contamination of products.
All wholesale premises have to have natural lighting or the appropriate artificial lighting in accordance with the prescribed conditions of keeping medical devices.
The size and equipping of premises is suitable for the nature of the medical devices and the scope of envisaged distribution.
All consignments are examined upon receipt to determine whether the packaging is damaged and whether it corresponds to the consignment order.
Medical devices requiring keeping under specific conditions are immediately identified and placed in the space that corresponds to the keeping conditions as stipulated by the manufacturer.
Medical devices are kept separate from other products, protected from light, moisture and inadequate temperature, in accordance with the prescribed storage conditions.
The space in which the medical devices are kept requires regular cleaning, and a record are kept with the date and time and manner of cleaning performed.
When specific temperature storage conditions are required for a particular medical device, it is necessary to monitor the temperature and keep records thereof, and storage areas are equipped with devices that indicate changes in temperature outside the stipulated range.
In handling stock, there should be a system to ensure stock rotation depending on the date of receipt or the date of expiry. It is compulsory to conduct regular controls of the functioning of the system.
Medical devices whose shelf-life has expired, that have damaged packaging, or for which there is a suspicion of contamination, are kept separately.
All deliveries of medical devices are accompanied by a document containing at least the following information:
- name of medical device;
- received or issued quantity and price of medical device;
- lot number or serial number of the medical device, and
- name and address of the supplier or recipient.
Prior to delivery, the wholesale distributor is obliged to verify whether the medical device has been properly labelled and is accompanied by instructions for use, if applicable.
Medical devices are transported in such a way that:
- their identification is not lost;
- adequate precautions are taken against spillage, breakage or theft;
- they are protected from unacceptable heat, cold, light, moisture, microorganisms or pests, or other adverse effects;
- the appropriate storage conditions are met as prescribed by the manufacturer.
The vehicle in which the medical devices are transported has to be clean and adequately equipped so as to enable the maintenance of special storage and keeping conditions.
If the wholesale distributor does not have its own transport vehicles, it is obliged to contract transport services in such a way that the service provider is obliged to abide by the requirements.
In the case of urgency, the wholesale distributor may enable urgent delivery of medical devices.
14. What information must be included in medicine and device labeling?
A) MEDICINAL PRODUCTS
The following particulars appear on the outer and immediate packaging of a medicinal product in the Croatian language or, where there is no outer packaging, only on the immediate packaging:
- the name of the medicinal product followed by its strength and pharmaceutical, and, if appropriate, whether it is intended for infants, children or adults; where the product contains up to three active substances, the international non-proprietary name (INN) is included, or, if one does not exist, another common name;
- the qualitative and the quantitative composition in active substances, using common names, for each dosage unit of the medicinal product, or depending on the pharmaceutical per volume or weight;
- the pharmaceutical and content in weight, volume or units of dosage;
- list of excipients of known action or efficacy and, in the event of medicinal products intended for parenteral or topical use or for ophthalmologic medicinal products, all excipients are indicated;
- the method of administration and, if necessary, the route of administration; space is provided for the prescribed dose to be indicated;
- a special warning that the medicinal product is stored out of the reach and sight of children;
- specific precautions, if necessary;
- clearly indicated expiry date (month and year);
- special storage precautions, if applicable;
- special waste management measures for unused medicinal products or waste materials;
derived from such medicinal products, if appropriate, along with instructions for the appropriate system for their collection;
- name and address of the marketing authorisation holder, or, where applicable, name of the authorised representative of the marketing authorisation holder;
- number of the marketing authorization;
- batch number;
- in case of over-the-counter medicinal products, the instructions for use of such medicinal products, including the indications, and
- dispensing of the medicinal product.
Medicinal products, with the exception of radiopharmaceuticals, have to have a safety indication on the packaging, the types of medicinal products that contain a safety label and the means of labeling the medicinal product with a safety label are regulated by the Delegated Commission Regulation (EU) 2016/161 of 2 October 2015 on a supplement to Directive 2001/83 / EZ of the European Parliament and of the Council by laying down detailed rules for the safety labels on the labeling packs of medicines for human use. Excipients are listed in accordance with a European Commission guideline.
Where the immediate packaging takes the form of a blister or in case of a small packaging, not all above-mentioned data are required.
Where the immediate packaging takes the form of a blister and it is placed in the outer packaging which complies with requirements of Medicinal Products Act, it has to contain at least the following information:
- name of the medicinal product of Medicinal Products Act;
- name of the marketing authorisation holder, or the name of the manufacturer;
- expiry date, and
- batch number.
In the event of a small immediate packaging that cannot contain all data it has to contain at least the following:
- name of the medicinal product and, if necessary, administration route;
- method of administration;
- expiry date;
- batch number, and
- content in weight, volume or units of dosage.
B) MEDICAL DEVICES
Each medical device is accompanied by the information needed to use it safely and properly, taking account of the training and knowledge of the potential users, and that identify the manufacturer.
This information comprises the data on the label or in the instructions for use of the medical device.
By way of derogation in duly justified and exceptional cases no such instructions for use are needed for medical devices that are set out by the Medical Devices Act, if they can be used properly and safely without them.
By way of derogation in duly justified and exceptional cases no such instructions for use are needed for in vitro diagnostic medical devices which if they can be used properly and safely without them.
The instructions for use and labelling of the medical device are in Croatian language and appear in a visible and legible and form.
Where the instructions for use and labelling are translated into Croatian language, the translation of the instruction for use and marking of the medical device are equally correspond to the original instructions for use and marking of the medical device.
The instructions for use of medical devices exclusively intended for use by medical institutions must be supplied in a language which is known by the user. The instruction for medical devices referred to in Article 3 paragraph 1 of the Commission Regulation (EU) No 207/2012 of 9 March 2012 on electronic instructions for use of medical devices, may be in electronic form in line with the provisions of the latter.
The CE marking of conformity appears in a visible, legible and indelible form on the device or its sterile pack, where practicable and appropriate, and on the instructions for use.
The CE marking has to be accompanied by the identification number of the notified body responsible for conformity assessment if the body concerned has been involved in the conformity assessment procedure.
15. What additional information may be included in labeling and packaging?
Only informations enacted by the Medicinal Products Act and its regulation may be included in labelling. Outer packaging and the package of medicinal product leaflet may contain symbols or pictograms approved by the Agency, to clarify certain information in accordance with the text of the summary of product characteristics that are useful for the user but excluding any elements of promotional nature.
16. What items may not be included in labeling and packaging?
A) MEDICINAL PRODUCTS
Informations and items not foreseen by the Medicinal Products Act and its regulations may not be included in labeling and packaging.
Therapeutic indications cannot be stated on the outer and immediate packaging of the product and in the package leaflet, if the product does not have a marketing authorisation as a medicinal product or a homeopathic medicinal product.
B) MEDICAL DEVICES
Informations and items not foreseen by the Medical Devices Act and its regulations may not be included in labeling and packaging.
It is prohibited to affix CE marks of conformity to medical devices if the medical device concerned does not meet the criteria laid down by Medical Devices Act.
It is prohibited to affix CE marks within the meaning of Medical Devices Act if the device concerned does not constitute a medical device.
It is prohibited to affix marks or inscriptions which are likely to mislead third parties with regard to the meaning or the graphics of the CE marking.
17. What are the restrictions and requirements for the marketing and advertising of medicines and devices?
A) MEDICINAL PRODUCTS
Advertising of medicinal products includes;
- advertising towards the population;
- advertising towards healthcare professionals who are authorised to recommend, prescribe or dispense medicinal products;
- advertising towards healthcare professionals;
- distributing samples;
- organising promotional meetings attended by persons authorised to recommend, prescribe or dispense medicinal products;
- organize professional and scientific congresses intended for healthcare professionals, and in particularly the payment of their travel costs, registration fees and accommodation at such meetings, and
- provision of support activities to professional associations and patient association, if medicinal products are promoted through such activities.
The following is not considered as advertising of medicinal products:
- labelling of medicinal products, summary of product characteristics and package leaflet;
- correspondence between healthcare professionals, representatives of the pharmaceutical industry and relevant marketing authorisation holders in promotion, to which materials are appended that do not serve for promotional purposes, and which is in response to a specific question pertaining to a specific medicinal product;
- informative notices on the facts and professional materials that, for example, pertain to changes in packaging, warnings of adverse reactions or other amended safety information, trade catalogues and price lists, under the condition that they contain no promotional claims on the medicinal product, and
- all unbiased, objective information about diseases, prevention or the available methods of treatment, including pharmacological measures, in which it is not permitted to single out any specific medicinal product.
Advertising of medicinal products includes any form of information which is designed to promote its prescription, supply, sale or consumption and which is provided in a written, oral, pictorial, audio, electronic, digital or any other form.
Medicinal products subject to medical prescription as well as medicinal products not subject to medical prescription may be advertised in scientific literature, at symposia and conferences and to healthcare professionals.
Medicinal products not subject to medical prescription may be advertised to the public.
The advertising of medicinal products subject to medical prescription to the public is prohibited. The prohibition contained does not apply to public health campaigns for the promotion of vaccination, seroprophylaxis and chemoprophylaxis programmes drawn by the Minister in accordance with the Act on the Protection of the Population against Communicable Diseases.
The advertising of any medicinal product unauthorised in Croatia, except at symposia and conferences and in scientific literature and provided that the procedure for granting of the marketing authorisation has been instituted and that only common name of the medicinal product is used, without any mentioning of the manufacturer, is prohibited. Restrictions do not apply to scientific and expert meetings held in Croatia.
When advertising homeopathic medicinal for which a simplified procedure for obtaining marketing authorization is conducted only the data specified in Medicinal Products Act may be used.
B) MEDICAL DEVICES
Advertising of medical devices within the meaning of Medical Devices Act means any activity designed to promote the prescription, sale or consumption of a medical device, in any written or oral form, using picture and sound, in electronic, digital or other form.
It is prohibited to advertise any medical device which does not meet the requirements laid down by Medical Devices Act, with the exception of the medical devices intended to be used in exhibitions, demonstrations, fairs etc. Such devices are provided a visible sign clearly indicating that they cannot be marketed or put into service.
Misleading advertising of medical devices are prohibited.
Medical devices which are intended for use exclusively by healthcare practitioners may be advertised but the advertising in such a case is targeted exclusively to a healthcare professional.
Advertising of medical devices is banned in case of information which:
- gives the impression that a medical device can guarantee recovery from the illness and that the health of the subject can be enhanced exclusively by using the advertised medical device, whereas the objective judgement is furnished by evidence;
- suggests that the health of the subject could be affected by not using the medical device that has been advertised;
- encourage the patients to abandon the generally accepted treatment procedures;
- is directed exclusively or principally at children;
- confuse by the use of scientific terms unknown to the general public for common health conditions;
- refers to a recommendation by scientists, health professionals or persons who are neither of the foregoing but who, because of their celebrity, could encourage the use of the medical device;
- suggests that the safety of the medical device is due to the fact that it is natural;
- could, by a description or detailed representation of a case history, lead to erroneous selfdiagnosis;
- refers, in improper, alarming or misleading terms, to claims of recovery;
- refers, in improper, alarming or misleading terms, pictorial representations of changes in the human body caused by disease, and
- assaults human dignity.
18. Where can medicines and devices be sold or delivered? Can medicines and devices be sold or delivered via post?
A) MEDICINAL PRODUCTS
Retail sale of medicinal products is carried out by business entities and private individuals authorised to engage in pharmacist activity in accordance with a special act as well as by specialised retail stores authorised by the Agency to engage in retail sale of medicinal products. Medicinal products subject to medical prescription are dispensed exclusively in pharmacies, while medicinal products not subject to medical prescription can be also dispensed in specialized retail sale outlets for medicinal products in line with the marketing authorisation granted by the Agency. If the medicinal product can be dispensed in specialized retail sale outlets for medicinal products, the Agency may determine restrictions in respect of its strengths and pack sizes.
Private individual and business entity engaged in pharmacist activity in Croatia may over the Internet offer for distance selling, in line with a special regulaton, medicinal products which are not subject to medical prescription.
Medicinal products not subject to medical prescription can be sold and delivered via post.
B) MEDICAL DEVICES
The retail sale of medical devices is performed by private individual and business entity who, have received authorisation for performance of pharmacy activities, and specialised shops for the retail sale of medical devices that have received a permit from the Agency for the retail sale of medical devices. Specialised shops may only sell those medical devices that meet all the requirements stipulated by the Medical Devices Act and are suitable for such sale with regard to their intended purpose, and the environment in which the medical devices are envisaged for use.
Business entities and private individuals engaged in pharmacy activity in Croatia, specialized retail stores selling medical devices and wholesale distributors may offer for sale medical devices via Internet (distance selling) in line with their line of business and in compliance with the separate rules.
Medical devices can be sold and delivered via post.
19. What are the restrictions and requirements for electronic marketing and advertising via email, by Internet, social media, and other channels?
Requirements and restrictions are the same for all channels of advertising. Advertising must comply with restrictions and requirements deccribed in question 17 of this chapter.
20. May medicines and devices be advertised or sold directly to consumers?
A) MEDICINAL PRODUCTS
The advertising of medicinal products products that are subject to medical prescription to the public is prohibited. Medicinal products not subject to medical prescription may be advertised to the public.
Retail sale of medicinal products is carried out by business entities and private individuals authorised to engage in pharmacist activity in accordance with a special act as well as by specialised retail stores authorised by the Agency to engage in retail sale of medicinal products.
B) MEDICAL DEVICES
In the retail of medical devices has to be engaged business entity and private individual who, in accordance with a separate law, has been authorised to carry out pharmacy activities and specialised retail stores selling medical devices who have been licenced by the Agency to carry out the activities involving the retail of medical devices.
Advertising of medical devices to public and directly to consumers is allowed.
21. How is compliance monitored?
A) MEDICINAL PRODUCTS
The supervision of the implementation of the provisions of Medicinal Products Act in respect of distribution and advertising of medicinal products is carried out by the pharmaceutical inspectorate of the Ministry of Health.
B) MEDICAL DEVICES
The pharmaceutical inspections regarding the implementation of the provisions of Medical Devices Act and the bylaws adopted on the basis of this Act is performed by pharmaceutical inspectors of the Ministry of Health.
22. What are the potential penalties for noncompliance?
A) MEDICINAL PRODUCTS
According to Medicinal products Act private individual or business entity is liable to a fine of between HRK 100,000.00 (approx. EUR 13,500.00) and HRK 150,000.00 (approx. EUR 20,200.00) for advertising medicinal products contrary to the provisions of Medicinal Products Act Act and the ensuing regulations and for claiming that the product has medicinal properties in the advertisement if the concerned product is not authorised as a medicinal product or registered as a traditional herbal medicinal product. For the same misdemeanours responsible persons of business entity are also be liable to a fine of between HRK 10,000.00 (approx. EUR 1,300.00) and HRK 15,000.00 (approx. EUR 2,000.00).
According to Medicinal Products Act private individual or business entity can also liable to a fine of between HRK 70,000.00 (approx. EUR 9,400.00) and HRK 100,000.00 (approx. EUR 13,500.00) for advertising homeopathic medicinal in a manner that not only the data specified in Medicinal Products Act were used. For these misdemeanours, responsible persons of business is also be liable to a fine of between HRK 7,000.00 (approx. EUR 900.00) and HRK 10,000.00 (approx. EUR 1,300.00).
B) MEDICAL DEVICES
A fine in the amount ranging from HRK 70.000.00 (approx. EUR 9,400.00) to HRK 100.000.00 (approx. EUR 13,500.00) is imposed on a business entity and private individual if they advertise about the medical device in contravention of the Medical Devices Act and if the advertisement on medical device contains information that are banned by the Medical Devices Act. For these minor offences the responsible person in the business entity will also be fined in the amount ranging from HRK 7.000.00 (approx. EUR 900.00) to 10.000.00 (approx. EUR 1,300.00).