Biosimilars & Biologics
Key legal info on biosimilars & biologics 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. Are biosimilar medicines considered the same as generic medicines in your country?
Biosimilar medicines are not the same as generic drugs (a drug that contains the same molecule as an existing non-biological medicine, such as aspirin). Namely, biological medicine, unlike non-biological medicines, cannot reproduce correctly (see the above-mentioned explanation). Biosimilar medicines have nothing to do with complementary or natural medicines or herbal medicines.
The generic medicinal product shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.
A biosimilar medicinal product is a medicinal product with a proven similarity in terms of quality, biological activity, safety and efficacy as the approved original biological medicinal product. Due to complex active substance structure and manufacturing procedure of biological medicinal products it is unlikely to produce a biological medicine with a completely identical active substance structure as the original biological medicine. Therefore, the standard approach in development and approval of generic chemical medicines, based on bioequivalence with original medicine, may not be applied to biosimilar medicinal products, but rather their similarity with original medicines should be proved through further studies during the product development and marketing authorisation procedure.
2. Are all biologic medicines, including biosimilar medicines patentable in your country?
Once EMA has thoroughly assessed their quality, efficiency and safety, the European Commission can approve biosynthetic medicines for marketing throughout the EU. Their availability then depends on the decision to place medicines on the market that the company brings together with the institution responsible for medicines and health care services in each EU country. In Republic of Croatia the institution responsible for medicines and health care services is called The Agency for Medicinal Products and Medical Devices (HALMED). It was established on October 1st, 2003. as a legal successor to the Croatian Institute of Medicines Control and the Croatian Institute of Immunobiological Preparations Control, albeit with a considerably broader scope of work. The Agency was established by the Republic of Croatia. Legal compliance of the Agency is supervised by the Ministry of Health. The Agency provides services pertaining to medicinal products, medical devices and homeopathic medicinal products in accordance with the primary and secondary legislation of the Republic of Croatia.
3. Is there a specific regulatory framework for the marketing authorization of biosimilar medicines in your country? If yes, what is the regulatory framework for the authorization of biosimilar medicines?
All biosimilar medicinal products currently approved in the Republic of Croatia have been authorised via centralised procedure for granting marketing authorisation, which means that the European Medicines Agency (EMA) scientifically reviewed the products and the European Commission has granted marketing authorisations. The quality, efficacy and safety assessment at the EMA is carried out at the highest scientific and technical level involving experts from all the EU Member States. The scientific opinion is adopted at the Committee for Medicinal Products for Human Use (CHMP) and the Pharmacovigilance and Risk Assessment Committee (PRAC). Within the scope of its work, the CHMP is additionally advised from working groups of experts with narrow specialisation in biological medicinal products (Biologics Working Party, BWP) and biosimilar medicinal products (Biosimilar Medicines Working Party, BMWP).
4. What kind of data package is needed to obtain approval for a biosimilar drug? Is this any different to the requirements for the original Biologics drug?
In order to obtain marketing authorisation, the manufacturer is required to perform comprehensive testing as evidence that the biosimilar medicinal product is very similar to the original biological medicinal product in terms of quality, safety and efficacy.
5. What are the requirements for the choice of the reference comparator product?
In cases where the reference medicinal product referred to in Article 29 paragraph 4 of the Promulgating the Medicinal Products Act is not authorised for marketing in the Republic of Croatia, the applicant for marketing authorisation of a generic product shall indicate the EU Member State in which the reference medicinal product is or has been authorised, as well as the date of the initial authorisation. In cases where the reference medicinal product is or has been authorised for marketing in the Republic of Croatia, on request of the competent authority of the EU Member State, the Agency shall within a month submit a certificate showing that the reference medicinal product either is or has been authorised for marketing in the Republic of Croatia, accompanied by the data on the general composition of the reference medicinal product and also, if required, by any other information from the medicinal product dossier.
In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided in Article 29 paragraphs 5, 6, 7 and 8 of this Act or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of variations in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, the marketing authorisation applicant referred to in Article 26 paragraph 1 of this Act shall be required to attach to the application the results of the appropriate pre-clinical tests and clinical trials in accordance with Article 26 paragraph 3 (k) of this Act.
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
Without prejudice to the regulations relating to the protection of industrial and intellectual property, the applicant referred to in Article 26 paragraph 1 of this Act shall not be required to provide the results of pre-clinical tests and of clinical trials, referred to in Article 26 paragraph 3 item (k) of this Act, 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.
7. How are the prices of biosimilar medicines regulated? Is this any different to the requirements for the original Biologics drug?
The price of the first biosimilar medicines proposed for listing should not exceed 80% of the cost of the drug with the same active ingredient (the same unprotected name) that is already on the list of medicines of the Institute.
The price for each next generic medicine proposed for placing on the list of drugs and for the biosimilar medicines biosynthesis drug proposed for inclusion on the list of medicines, should not exceed 95% of the cost of the same unprotected name as defined in this article.
8. What is the reimbursement policy for biosimilar medicine? Is this any different to the requirements for the original Biologics drug?
The share of expenditures on reimbursement of biosimilars in the total pharmaceutical budget differed between the EU countries, with lowest observed value for Croatia. In Croatia only Budget Impact Analysis (BIA) is required for biosimilars, and in certain cases, the Croatian HALMED Agency performs Health technology assessment or (HTA) evaluation.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
Usually, the price difference between the biosimilar and originator medicine is set at a lower percentage rate than that between the generic and originator (e.g., 30%—generics, 15%—biosimilars in Croatia. European countries tend to in general apply similar pricing policies for generic and biosimilar medicines.
10. What is the legal framework for biosimilar medicines prescribing (clinical decision maker) and dispensing (pharmacy level, hospital or retail)? Is this any different to the requirements for the original Biologics drug?
Substitution and interchangeability are generally allowed, although they are at the discretion of the physician after a clinical assessment. Decision-making process for purchasing and procurement always involve a committee involving medical or scientific advice. There are not any quotas on biological drugs.
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
Substitution refers to the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber, in Croatia it is not possible, and there are no propositions about switching to pharmacy level substitution.
12. What are the post – authorisation requirements (including pharmacovigilance, risk management plans, post-approval studies) for biosimilar medicines? Is this any different to the requirements for the original Biologics drug?
After obtaining a marketing authorisation for a medicinal product, the marketing
authorisation holder shall be required to:
- take account of scientific and technical progress and introduce any variations that may be required to enable the medicinal product to be manufactured and checked by means of
generally accepted scientific methods,
- forthwith provide the Agency with any new information which might entail amendments to the data, documents and files of the medicinal product provided in the frames of the marketing authorisation procedure or the arbitration proceedings in the European Union and/or the ordinance referred to in Article 26 paragraph 7 of this Act,
- forthwith inform the Agency of any restriction or prohibition imposed by the competent authorities of other states in which the medicinal product is marketed and of any other new information which might influence the benefits and risks of the medicinal product concerned. The marketing authorisation holder shall supply the Agency with both positive and negative results of clinical and other studies in all indications and populations of subjects, whether or not included in the marketing authorisation, as well as data on the use of the medicinal product where such use is not covered by the marketing authorisation,
- ensure that the product information is kept up to date with the current scientific knowledge, including the conclusions of public reports relating to assessment of the medicinal product dossier and recommendations of the EMA made public by means of the European medicines web-portal.
In the case referred to in paragraph 1 of this Article the Agency may require that the
marketing authorisation holder initiates the procedure for variation(s) approval or to amend, ex officio, the authorisation for placing the medicinal product on the market.
In order to enable continuous assessment of the risk-benefit balance, the Agency may at
any time ask the marketing authorisation holder to forward data demonstrating that the risk benefit balance of the medicinal product remains favourable.
The Agency may at any time ask the marketing authorisation holder to submit a copy of
the pharmacovigilance system master file. The marketing authorisation holder shall submit the copy at the latest seven days after receipt of the request.
13. Are there specific policies and requirements in terms of biosimilar medicines labelling in the event of second medical use patents? Is this any different to the requirements for the original Biologics drug?
Labels on medicinal products contain information for pharmacists, physicians and patients. This information is presented in the Summary of Product Characteristics (SmPC), the Patient Leaflet (PL) and the immediate label on the outer product packaging, referred to as ‘labelling’. Once authorized, the European Medicines Agency (EMA) applies a ‘same-label’ (generic) approach to biosimilar product labels. This means that the information on the labelling of the biosimilar should be a copy of the approved labelling of the reference product, with the exception of the pharmaceutical particulars. Section 5.1 of the SmPC, a document not usually available to patients, will include a statement declaring that the product is a biosimilar, but this is the only part of the labelling where this information can be found. Neither PLs nor the immediate labels contain this information.
14. Have there been any significant legal/judicial developments in relation to biosimilars in your country? (Including but not limited to IP, procurement, competition, misleading information campaign, access to reference comparator product)
There have not been any significant developments in relations to biosimilars but are expected.
15. Are there proposals for reform or significant change to the legal, regulatory, procurement of biosimilars? If yes, when are they likely to come into force?
No, there are no proposals for comprehensive reform that would redact the legislation of biosimilars.