The regulatory regimei Classification
Definition of medicinal products under ZZdr-2 follows the definition as provided by Article 1 of the Directive 2001/83/EC. If a product after considering all its characteristics may fall in the category of a medicinal product under ZZdr-2 as well as under the definition of a product subject to other regulations, if in doubt the rules of ZZdr-2 shall apply to such product. ZZdr-2 contains general guidance on which elements shall be considered when determining whether a product shall be classified as a medicinal product. Whether the product shall be classified as a medicinal product shall be determined by JAZMP in an administrative proceeding, initiated upon an application of the manufacturer or the seller of the product or ex officio.
For medical devices, the rules of Regulation 2017/745/EU apply to classification of medical devices.ii Non-clinical studies
ZZdr-2 contains very limited provisions on analytical and pre-clinical testing of medicinal products. According to ZZdr-2, analytical testing shall be carried out in accordance with the principles and guidelines of good manufacturing practice. Pre-clinical toxicological and pharmacological testing shall be carried out in accordance with principles and guidelines of good laboratory practice. For further rules on methods and procedure of analytical, pre-clinical and clinical testing as well as content of documentation on quality, safety and efficacy of a medicinal product, Slovenian law8 references the provisions set forth in Annex I to the Directive 2001/83/EC.
As regards animal welfare, animal torture is in general prohibited and treating an animal cruelly or causing it unnecessary suffering is considered a criminal act under the KZ-1.9 Therefore, specific rules to protect animal welfare as regulated by ZZZiv10 should be respected when conducting studies in animal models. One of the purposes for which experiments on animals are permitted by ZZZiv is translational or applied research intended for deterrence, prevention, diagnosis or treatment of diseases, poor health conditions, other pathological changes or their effects on humans, animals or plants (Article 21.a(b) of ZZZiv). Experiments on animals may only be carried out by organisations approved in accordance with ZZZiv (Article 20.a(1) of ZZZiv) and which have obtained an experiment authorisation (Article 21 of ZZZiv) issued by the Administration for Food Safety, Veterinary Sector and Plant Protection. According to Article 21 of ZZZiv, a joint experiment authorisation can be issued for multiple generic projects carried out by the same organisation to meet the prescribed requirements or for manufacturing or diagnostic purposes by means of established methods. If the organisation carries out the experiment in violation of the experiment authorisation and if this compromises the welfare of animals, the experiment authorisation may be revoked. The organisation may re-submit an application three months after the decision revoking the approval for the project became enforceable.iii Clinical trials
According to Article 34 of ZZdr-2, a medicinal product may be submitted to clinical trial only after the submission of the results on analytical and non-clinical pharmacotoxicological testing of the medicinal product and if the medicinal product being investigating has no impact on the subject's germ line genetic identity. A clinical trial shall be conducted in accordance with the principles and guidelines of good clinical practice adopted and published by the European Commission, the principles of ethics in human medicine as well as in compliance with the mandatory and guaranteed protection of personal data.
In general, a clinical trial must be notified to JAZMP prior to its commencement (Article 35(2) of ZZdr-2). However, clinical trials of medicinal products for human use intended for gene therapy, somatic cell therapy, including xenogenic cell therapy and all medicinal products containing genetically modified organisms require prior authorisation of JAZMP (Article 35(3) of ZZdr-2). In both cases, an opinion of the National Medical Ethics Committee (abbreviated in Slovenian as KME) shall be obtained prior to the respective application to JAZMP (Article 37(3) of ZZdr-2). A clinical trial may be initiated only if in the opinions of JAZMP and KME determine that the anticipated benefit in treatment and to the public health justify the risks and may be continued only if the fulfilment of said condition is continuously monitored (Article 4 of the Rules on Clinical Testing).11 Non-interventional clinical trials shall also be notified to JAZMP and also require a positive opinion by the KME (Article 40(1) and (2) of ZZdr-2).
The application to notify or to seek approval for clinical trial shall be filed by the sponsor established in the EU or if the sponsor is not established in the EU, its representative established in the EU (Article 35(1) of ZZdr-2). The applicant shall be required to insure its liability for potential damages occurred as a result of the clinical trial (Article 36 of ZZdr-2). According to the Rules on Clinical Testing, the sponsor shall be liable to pay damages and compensation for adequate care to the trial subject in case of damage that occurred as a consequence of the clinical trial.
According to ZPacP,12 a patient's prior free will and informed consent is required for the patient's participation in medical research (Article 26(3)(5) in connection to Article 26(2) and Article 20 of ZPacP). More detailed rules on providing informed consent are provided by the Rules on Clinical Testing.iv Named-patient and compassionate use procedures
There are certain exceptions to the general requirement for the medicinal product to obtain a marketing authorisation prior to its marketing. In certain cases, a provisional authorisation for marketing may be granted by JAZMP (Article 20(3) of ZZdr-2):
- on the basis of a request of the attending physician and an opinion of the responsible person of the hospital or institute, or on his or her personal responsibility, for the needs of one or more individual patients;
- in exceptional cases (infections, epidemics, pandemics, poisoning, radiation, etc.), for the purpose of implementing protective measures or for other reasons that are in the interest of public health protection;
- for a medicinal product listed among the essential or indispensable medicinal products where no other equal medicinal product with marketing authorisation has been placed on the market or such is not available on the market in Slovenia; or
- for medicinal products provided for in the budget of Slovenia in exceptional circumstances (such as natural disasters or war) if no medicinal product with the same composition and marketing authorisation is marketed in Slovenia.
Compassionate use of a medicinal product is possible upon prior approval of JAZMP, which requires a prior opinion of the Committee for Medicinal Products for Human Use at the European Medicines Agency (based on Article 83 of the Regulation 726/2004/EC) and, in case the product is subject to a clinical trial, a positive opinion by the KME. A medicinal product which constitutes a significant therapeutic, scientific and technical innovation and is intended for a group of patients with a chronic or severely debilitating disease that cannot be satisfactorily treated with medicinal products that have marketing authorisations may be eligible for the compassionate use authorisation if a marketing authorisation under the EU centralised procedure is pending for such product or the product subject to clinical trial to obtain a marketing authorisation under the EU centralised procedure, and is authorised in a third country with equivalent requirements as regards the quality, safety and efficacy of the medicinal product. The costs for the medicinal product in the compassionate use programme and costs for its supply during the term of the programme and in certain cases for one year after expiry of the programme are paid by the manufacturer of the medicinal product (Article 41(2) of ZZdr-2).v Pre-market clearance
Prior to marketing of the medicinal product in Slovenia, a marketing authorisation or an authorisation for parallel distribution shall be obtained (Article 20(1) of ZZdr-2).
A centralised marketing authorisation may be applied for and granted by the European Commission pursuant to the Regulation 726/2004/EC. The national authority JAZMP may grant a marketing authorisation valid in Slovenia based on national proceedings, mutual recognition proceedings or decentralised proceedings (as per Chapter 4 of the Directive 2001/83/EC). Slovenian law implements the provisions of Directive 2001/83/EC with respect to marketing authorisation procedures and requirements. A marketing authorisation for medicinal products may be applied for by an entity established in the EU, who is either the manufacturer of the medicinal product or an entity that entered into a written contract with the manufacturer (Article 43(1) of ZZdr-2).
Fees of JAZMP for grant of marketing authorisations vary depending on type of proceeding. For example, for grant of a marketing authorisation of an original product under decentralised proceedings where Slovenia is (1) the reference member state, a fee of €34,950 net applies; or (2) a concerned member state, a fee of €3,675 net applies.
As per Article 68 of ZZdr-2, the documentation enclosed with an application for the acquisition, variation or renewal of a marketing authorisation is the property of the applicant and a trade secret, with the exception of data stated in the marketing authorisation, the summary of the medicinal product characteristics, package leaflet and labelling. However, according to the practice13 of the Slovenian Administrative Court, said provision does mean that information available in the administrative file shall not be subject to disclosure under the rules regulating freedom of information requests (ZDIJZ).14 According to Article 6(1)(2) of ZDIJZ, information that is defined as a trade secret shall generally not be provided under the freedom of information request. However, access to the requested information shall be granted if public interest disclosure prevails over the public interest or interest of other persons not to disclose the requested information. According to the practice of the Administrative Court, the test of public interest shall be made accurately and deliberately and exceptions to providing information based on freedom of information requests shall be interpreted restrictively. The court referred to the policies of the European Medicines Agency (EMA) relating to which documents and information are being disclosed to the public as standards that should be taken into account when applying the public interest test.
JAZMP does not systematically publish public assessment reports on medicinal products authorised under national proceedings or under mutual recognition proceedings or decentralised proceedings where Slovenia is the reference member state. Some public assessment reports for medicinal products where Slovenia is the reference member state are published on the website of the Heads of Medicines Agencies.15
Procedures relating to medical devices are regulated by Regulation 2017/745/EU. According to Slovenian national regulation16 implementing said EU regulation, the documentation to be submitted for assessment of conformity of medical devices shall be either in Slovenian or in English.vi Regulatory incentives
Patent term extension in the form of a supplementary protection certificate (SPC) is available for medicinal products in accordance with Regulation 469/2009/EC. SPCs are applied for with and granted by the Slovenian Intellectual Property Office.
According to Article 45 of ZZdr-2, data and market exclusivity are available for originator products under the 8 + 2 + 1 principle mirroring the provisions of Article 14(11) of Regulation 726/2004/EC.
Incentives relating to orphan medicinal products are regulated with Regulation 141/2000/EC. Incentives relating to paediatric use are regulated by Regulation 1901/2006/EC.
Regulatory approval process is not linked to potential patent rights or the rights arising from a supplementary protection certificate.
A Bolar-style exception to patent protection is provided by Article 45(9) of ZZdr-2, according to which carrying out of studies necessary to comply with the requirements of ZZdr-2 and other requirements related to the acquisition of marketing authorisation shall not be deemed to be a violation of patent rights or the rights arising from a supplementary protection certificate for a medicinal product.vii Post-approval controls
In respect of the post-approval requirements (such as the requirement for the marketing authorisation holder to take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods), Article 62 of ZZdr-2 implements the provisions of Article 23 of the Directive 2001/83/EC.
According to Article 64 of ZZdr-2, the marketing authorisation for a medicinal product shall be varied, suspended or revoked by JAZMP in certain instances, such as that the risk:benefit ratio of the medicinal product is not favourable, as is evident from the periodic safety update report or other data from the pharmacovigilance system, or incorrect or incomplete data were presented for authorisation, etc.
When any of the requirements of a manufacturing authorisation are not met, JAZMP shall suspend or revoke the marketing authorisation for an individual medicinal product, a group of medicinal products or all medicinal products that are manufactured on the basis of that manufacturing authorisation.
A marketing authorisation may be transferred to an entity fulfilling the legal requirements for a marketing authorisation holder (Article 70(1) of ZZdr-2).viii Manufacturing controls
Manufacturing of medicinal products requires a manufacturing licence. A manufacturing licence can be applied for by entities with a registered seat in Slovenia (Article 94(1) of ZZdr-2). A legal entity seeking to obtain a manufacturing licence shall fulfil the requirements with respect to personnel, premises, installations and equipment for the manufacture, control, storage and marketing of medicinal products, in accordance with the principles and guidelines of good manufacturing practice (GMP). A GMP certificate shall be issued following an inspection at the latest in 15 days after the manufacturing licence has been granted.
There is no automatic or simplified process of transfer of manufacturing licences in case of transfer of ownership of manufacturing facilities. The transferee shall apply for a new licence.ix Advertising and promotion
With respect to the advertising of medicinal products, Slovenian law distinguishes between advertising to the general public on one hand and to the expert public on the other hand. Said terms are defined in the Regulation on Advertising of Medicinal Products: 'general public' means layman groups and individuals who are not part of the expert public, while 'expert public' means persons authorised to prescribe and dispense medicinal products (Article 3 of the Regulation on Advertising of Medicinal Products).17
It is prohibited to advertise prescription-only medicinal products to the general public (Article 148(1) of ZZdr-2). However, JAZMP may allow manufacturers of medicinal products to carry out vaccination campaigns with the necessary information on the vaccines included in the programme for vaccination and protection by means of medicinal products.
Prescription-only medicinal products may be advertised to the expert public in expert publications and with the direct informing of persons authorised to prescribe and dispense medicinal products, and on an exceptional basis, by providing samples (Article 149(1) of ZZdr-2). The issue of providing samples is discussed in some more detail below.
Slovenia has used the discretion provided by Article 96(2) of the Directive 2001/83/EC, which allows Member States to place further restrictions on the distribution of samples of certain medicinal products. Article 22 of the Regulation on Advertising of Medicinal Products provides under which conditions samples of prescription-only medicinal products may be provided. It does not provide anything with respect to samples of over-the-counter products. It is not completely clear what that should mean for over-the-counter products. For the correct interpretation of the provisions of Slovenian laws, the provisions of the respective EU laws shall also be considered. The issue of samples is regulated mainly by Article 96(1) of the Directive 2001/83/EC, with respect to which the Court of Justice of the European Union (CJEU) delivered a judgment in case C-786/18 ratiopharm GmbH v. Novartis Consumer Health GmbH on 11 June 2020. The CJEU ruled that Article 96(1) of the Directive 2001/83/EC is to be interpreted as meaning that pharmaceutical companies may not distribute medicinal products that are available only on prescription to pharmacists. However, it also ruled that on the other hand, that provision does not preclude distributing free samples of non-prescription medicinal products to pharmacists. It is a well-established principle of EU law and practice of the CJEU that in applying national provisions that are introduced to implement a directive, national law must be interpreted in the light of the wording and the purpose of the directive. According to the case law of the CJEU, the Directive 2001/83 brought about complete harmonisation in the field of (advertising of) medicinal products and lists expressly the cases in which Member States are authorised to adopt provisions departing from the rules laid down by that directive.
When conducting inspections of the operations of holders of marketing authorisations, in 2019 JAZMP focused also on the review of any patient support programmes (PSP) that were conducted by pharmaceutical companies. According to a statement published by JAZMP,18 inspections carried out by JAZMP revealed that some PSPs carried out by pharmaceutical companies, by financing the monitoring of patients, the advising of patients or the administration of their products for parenteral use at the patient's home via healthcare providers that the pharmaceutical companies engage, are to be considered advertising of prescription medicinal products, which is not in accordance with the rules on advertising of medicinal products.
Rules relating to sales promotions and enabling healthcare professionals to attend scientific meetings are discussed in some more detail in Section V.
According to Article 10 of the Regulation on Advertising of Medicinal Products, the advertising materials shall be in Slovenian. In areas where the Italian or Hungarian minorities live, the materials may also be in the language of the respective minority. However, literature enclosed with the advertising materials may also be in its original language. In international scientific meetings taking place in Slovenia, advertising materials may be also in the language in which the event is held or in the languages of the participants of the event.
As regards medical devices, according to Article 58 of ZMedPri it shall be prohibited to advertise medical devices that do not comply with the requirements of ZMedPri. However, medical devices that are not compliant with ZMedPri may be shown at fairs, exhibitions, presentations and similar events, provided that they are adequately marked as not being for sale or to be put to use. Medical devices used exclusively to perform medical activities may be advertised to the expert public. However, the definition of expert public differs from the one applicable to advertising of medicinal products. In relation to advertising of medical devices, 'expert public' shall mean healthcare professionals as defined by the act governing healthcare activity. Samples of medical devices may be provided (Article 59(4) of ZMedPri), subject to certain rules set forth by the Rules on Medical Devices.19x Distributors and wholesalers
Wholesale distribution of medicinal products requires a wholesale licence. A wholesale licence can only be applied for in Slovenia by entities with a registered seat in Slovenia (Article 94(1) of ZZdr-2). However, wholesalers licensed in other EU counties may perform wholesale activities in Slovenia based on prior notification of the JAZMP (Article 105(3) of ZZdr-2).
There are three types of wholesale licence available:
- full scope activity, which encompasses a licence for wholesale distribution of all medicinal products that may be traded in accordance with ZZdr-2 to all relevant counterparties: other wholesalers, retail sellers, healthcare organisations, social care institutions and the Slovenian army if such providers and institutions have organised pharmacies or an established system for the receipt, storage and traceability of medicinal products and a responsible person with adequate qualifications;
- contact-limited activity, which encompasses a licence for wholesale distribution of all medicinal products that may be traded in accordance with ZZdr-2 only to other wholesalers; and
- product-limited activity, which encompasses a licence for wholesale distribution of a restricted scope of medicinal products (i.e., it only covers the wholesale distribution of specified medicinal products, to all relevant counterparties (see Section a)).
Wholesale distribution of medical devices may be carried out by entities that fulfil the conditions for carrying out the activity of trade in general (Article 52(1) of ZMedPri). A notification of the activity with JAZMP is required for wholesale distribution of medical devices. Such notification is to be provided in 15 days after start of the relevant activity (Article 52(2) of ZMedPri).xi Classification of products
There are various classifications of medicinal products, one of them being classification into prescription-only or over-the-counter medicinal products. Certain specific rules apply to each category of medicinal products. Prescription-only medicinal products may only be sold or dispensed in pharmacies, while over-the-counter medicinal products may be sold in pharmacies or specialised shops. Specific rules on advertising of each category of products are summarised in Section II.ix. Some further classifications relevant to reimbursement are discussed in Section III.xii Imports and exports
Import of medicinal products from non-EU/non-European Economic Area (EEA) countries to Slovenia is an activity that is from a regulatory point of view considered a step in the manufacturing process. As such, it requires a manufacturing licence. Export of medicinal products to a non-EU/non-EEA country on the other hand is an activity that is from a regulatory point of view considered wholesale distribution of medicinal products. As such, the activity requires a wholesale licence. Trade with medicinal products with the EU or the EEA, both to and from Slovenia, also requires a wholesale licence.
Medical devices may be imported to Slovenia if they are compliant with the requirements of ZMedPri and in case the manufacturer is established in a non- EU/EEA country, the manufacturer has appointed a representative established in the EU with respect to such medical devices (Article 54(1) of ZMedPri). A notification of the activity with JAZMP is required for import of medical devices under ZMedPri. Such notification is to be provided in 15 days after start of the relevant activity (Article 54(5) in connection with Article 52(2) of ZMedPri). The entity importing medical devices shall fulfil the conditions generally required to carry out the activity of trade (Article 54(2) of ZMedPri) and certain specific conditions provided by ZMedPri.xiii Controlled substances
Controlled substances are regulated by ZPPPD,20 which sets out the conditions under which the production of and trade in illicit drugs and the possession of illicit drugs are permitted. The classification list of illicit drugs shall be adopted by the Slovenian government. The products shall be classified into one of three groups based on the risk they pose to human health, and with regard to their use in medicine (groups I, II and III, group I being the most hazardous one).
According to Article 7 of ZPPPD, the production of, trade21 in and possession of illicit drugs from group I may be performed exclusively for scientific research and for educational purposes. Illicit drugs from groups II and III may be produced, released into circulation or possessed for medical, veterinary, educational and scientific research purposes. Said activities require a licence issued by the minister of health. Transit of illicit drugs across the customs territory of Slovenia shall be permitted only if the consignment has an export licence from the state from which the illicit drugs are being exported and an import licence from the importer state.xiv Enforcement
Supervision of the implementation of regulatory requirements is carried out by pharmaceutical inspectors of JAZMP and the Slovenian customs authority (the Financial Administration of the Republic of Slovenia; abbreviated in Slovenian as FURS) is tasked with the supervision of import of medicinal products, with JAZMP providing expert support. For medical devices, supervision is carried out by the JAZMP inspectors, except for certain issues relating to trade with medical devices, which are supervised by the market inspectorate.
In case of non-compliance with regulatory requirements, there are two types of proceedings that may be initiated by the pharmaceutical inspector: administrative proceedings and misdemeanour proceedings.
In administrative proceedings, the pharmaceutical inspector may by way of an administrative decision impose measures necessary to implement the regulatory requirements, such as:
- prohibit the performance of the activity as a result of non-compliance with prescribed conditions;
- prohibit the trade, order the destruction of, or recall certain batches of medicinal products in certain cases;
- prohibit the entry or import of a medicinal product that is not covered by an appropriate JAZMP authorisation;
- order the removal or destruction of the materials used for illegal advertising of medicinal products; and
- prohibit the advertising or provision of information that is in conflict with the provisions of ZZdr-2, etc.
If the non-compliance amounts to a misdemeanour, the pharmaceutical inspector may initiate misdemeanour proceedings. ZZdr-2 distinguishes between misdemeanours and severe misdemeanours. For the former, the legal entity that committed the misdemeanour may be punished by a fine from €800 to €4,000. The responsible individual of the legal entity may be fined from €200 to €1,000. A legal entity that committed a serious misdemeanour may be punished by a fine from €8,000 to €120,000. The responsible individual of the legal entity may be fined from €500 to €5,000.
Fines for misdemeanours of legal entities relating to medical devices range from €1,000 to €10,000 and from €15,000 to €150,000, respectively, depending on the type of misdemeanour. The ranges of fine for the responsible individuals of the legal entity are from €200 to €2,000 and from €300 to €3,000, respectively.