Orphan Drugs & Rare Diseases
Orphan drugs & rare diseases in Croatia – a legal guide. 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 definition of Rare Diseases in your country?
Simply put, an orphan drug is indicated for the treatment of a very rare disease. Such diseases are often caused by genetic defects and therefore children and newborns are affected to a great extent. Rare diseases are defined as life threatening diseases or diseases that may lead to chronic weaknesses, affecting maximally five out of 10,000 people in the EU. In other words, between 27 and 36 million people in the EU are affected by a rare disease.
2. Does the designation of ‘Orphan Drug’ exist in your country? (Does it correspond with the definition of Rare Diseases?)
Since Croatia is an EU member, all EU regulations are directly applicable, thus Regulation (EC) 141/2000 (so called “Orphan” Regulation) and Regulation (EC) 847/2000 are binding in their entirety and directly applicable in all Member States. A product can gain orphan drug status if it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10,000 people in the EU. A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish: that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the Community and that without incentives it is unlikely that the marketing of the medicinal product in the Community would generate sufficient return to justify the necessary investment. Also the product shall be designated as an orphan drug if there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the Community or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.
3. What is the regulatory framework for the authorization of an Orphan Drug? (Is this regulatory framework based on Rare Disease status or can it alternatively be based on Orphan Drug foreign status?)
The Regulation (EC) 141/2000 also establishes the Committee for Orphan Medicinal Products (COMP) within the European Medicines Agency (EMA), which is responsible for examining applications for orphan medicinal product designations. Regulation (EC) No 726/2004 provides the legal framework for the centralised authorisation and supervision of medicines for human and veterinary use. It determines that all marketing authorisations for orphan medicines in the EU should follow the centralised authorisation procedure and that the Committee for Medicinal Products for Human Use (CHMP) can issue guidance regarding compassionate-use programmes. After finalising the designation procedure, the sponsor needs to apply for an authorisation to place the product on the market.
4. Does your country have provisions for relaxed clinical trial/scientific evidence requirements in respect of Orphan Drugs as compared to other drugs?
The overall procedure for designation as an orphan drug (for the entry into the Community register for orphan medicinal products), in theory takes approximately six to eight months until the designation is granted. The whole process starts with an application for designation by the sponsor. All documents and information necessary for applying are more or less broadly formulated. The exact time of filing the application is not fixed; the only thing to keep in mind is that one has to apply for an orphan drug designation before making the marketing authorisation application.
The addressee of that application is the EMA. The EMA verifies the validity of the application and prepares a summary report to the Committee for Orphan Medicinal Products (COMP) which is set up within the agency. The COMP has to submit an expert’s opinion within 90 days of receiving the valid application. If everything goes according to plan, and there are no discrepancies within the COMP, the EMA forwards this opinion to the European Commission, which in turn has to render a decision within 30 days – as long as COMP’s opinion and the Commission’s decision correspond.
5. Is there an expedited pathway for Orphan Drugs?
In the EU, conditional marketing authorization was instituted in 2006 and the requirements are as follows: (1) It must fulfill an unmet medical need; (2) it must be applicable to life-threatening, serious, or emergency diseases, or orphan products; (3) The company must be able to provide clinical data comprehensively; and (4) There must be a positive benefit/risk balance. Conditional marketing authorization is active for one year only and annual renewal of the approval will continue until the EMA converts the conditional approval to standard authorization. In addition, conditional approval is applicable to applications of initial marketing authorization only, and efficacy supplement applications are beyond the scope of the conditional approval.
6. Are foreign marketing authorizations recognized in your jurisdiction for Orphan Drugs? If yes, marketing authorizations from which countries are recognized?
The European Medicines Agency (EMA) is responsible for the scientific evaluation of marketing authorisation applications for all orphan medicines in the European Economic Area (EEA), as they fall under the mandatory scope of the centralised procedure. The marketing authorisation is valid in the whole European Union. The sponsor does not need to apply for an authorisation in all – still – 28 Member States separately. It will have to be seen if and how that will change for the UK, with Brexit on the horizon. However, the granting of a marketing authorization (the list of marketed orphan drugs in Europe) does not mean that the drug is available in all EU Member States. The marketing authorization holder must decide in advance on his commercialization within each country and only then the remedy goes through the necessary national procedures to meet the conditions for the refund and often its price.
7. Can Orphan Drugs be reimbursed? If so, is there a specific reimbursement procedure for Orphan drugs?
The objective is to assess shares of reimbursed orphan drugs and agreement in reimbursement decision-making in different European Union member states as well as to define odds for reimbursement influenced by the presence of conditional approval or exceptional circumstances granted by the European Medicines Agency (EMA) or by type of disease. Access to reimbursed orphan drugs varies significantly across EU countries. The highest, substantial agreement in reimbursement decisions was observed between Italy and Spain and the lowest between Germany and England. Conditional approval and approval under exceptional circumstances were significant negative predictors of reimbursement in some countries and they were significantly associated with the type of the disease (oncology or metabolic).
8. How are the prices of Orphan Drugs regulated?
Pricing and accessibility of orphan drugs varies among countries in the EU. Although orphan designation and marketing authorisation is at a European level, pricing and reimbursement are on a national level, often driven by health technology assessment (HTA) outcomes and with variable impact from external reference pricing. In these HTAs, evidence requirements, pricing and reimbursement decision frameworks, and budget ceilings vary. Also, national responsibilities for price listing and the process in which prices are granted vary widely. As a consequence, prices and levels of access may vary.
9. In case of reference price based on a basket of countries, what countries are included?
The basis for determining the comparative price of a wholesale drug is the wholesale price of the same medicine (medicine of the same generic name and of the same pharmaceutical form) in Italy, Slovenia and the Czech Republic, and if there is no information on the prices of medicines for one or more countries, then the prices of medicines in Spain and France are used for comparison.
10. Have there been any significant legal/judicial developments in relation to Orphan Drugs in your country?
There is no national legislation that applies only to Orphan Drugs and that unites all legal provisions about Orphan Drugs, because the aforementioned EU regulations are directly applicable and are a part of domestic law.
Medicines for the treatment of symptoms of rare diseases very often belong to the groups of innovative and especially expensive drugs, that is, a separate group of “orphan” medicines. Croatia adopted new Ordinance on the criteria for placing medicinal products on the list of medicinal products of the Croatian Health Insurance Fund (CHIF). The adopted Ordinance did not clearly define the arrival of orphan medicines on the CHIF list, and by restricting the availability of the arrival of innovative medicines and extending the indications of medicines in the CHIF list, it limits the availability of treatment. However, Orphan drugs problem is in the vision of the Croatian Government. National Program for Rare Diseases 2015-2020 was adopted at the session of the Government, held on March 5, 2015. The program encompasses nine strategic areas of activity: education and information for professionals, people with illness and wider population, prevention and early detection of rare diseases, integrated health and social protection and promotion of rare diseases.
11. Are there proposals for reform or significant change to the regulation of Orphan Drugs? If yes, when are they likely to come into force?
The Regulation (EC) 141/2000 (Orphan Drug Regulation) which has – nowadays, rather surprisingly – only undergone one amendment in 2009. Considering the regulation has been in force for 20 years already without any major changes, it seems that the European legislator has succeeded in passing a profound and mature law that is worth taking a closer look at. At this moment there are no proposals for reform or significant change to the Regulation. However, on the national scale, it is still not foreseen by the National program for Rare Diseases 2015-2020 to pass the law related to Orphan Drugs. The highlights of the National program that are pointed out as the main problems in Croatian system of Orphan drugs that need to be solved are: improving the knowledge and availability of rare disease information, support for the development of rare diseases registers and their permanent financing, supporting the work and development of network of reference centres and relevant scientific organizations for rare diseases, improving availability and quality of health care (diagnosis, treatment and prevention) for people with rare diseases, ensuring availability of medications for rare diseases, improving the realization of social rights of rare diseases, empowering Associations of Rare Diseases, encouraging scientific research in the field of rare diseases, international networking and cooperation in the field of rare diseases.