Orphan Drugs & Rare Diseases
An intro to the legal situation for orphan drugs and rare diseases in Czech Republic. Prepared in association with PRK Partners, a leading law firm in Czech Republic, this is an extract from The Pharma Legal Handbook: Czech Republic, available to purchase here for GBP 99.
1. What is the definition of Rare Diseases in your country?
The relevant Czech regulation defines rare diseases as those with a very low incidence in the population, within the meaning of the relevant EU regulation. This refers to the definition from Article 3 of the directly applicable regulation (EC) No 141/2000 on orphan medicinal products (“Regulation 141”).
So, under Czech law a rare disease is a life-threatening or chronically debilitating condition affecting not more than five in 10,000 persons in the EU.
2. Does the designation of ‘Orphan Drug’ exist in your country? (Does it correspond with the definition of Rare Diseases?)
Since Regulation 141 is directly applicable in the Czech Republic, Czech law uses the definition of orphan drugs from Article 3 of the Regulation 141 as well.
The definition for orphan drugs (in Czech: léčivé přípravky pro vzácná onemocnění) corresponds to some extent with that of rare disease (in Czech: vzácná onemocnění). However, the definition of an orphan drug is broader when it states that the sponsor of a medicinal product wishing to designate it as an orphan drug must establish that the product is either (i) intended for a rare disease (see the definition in question 1. above) or (ii) intended for another serious disease, while the investment in the product without being designated as an orphan drug would otherwise likely be unprofitable.
Moreover, a medicinal product can be designated an as orphan drug only if (i) no satisfactory method exists for diagnosis, prevention or treatment of the (rare) disease, or (ii) a method exists, but the medicinal product in question would be of significant benefit to those affected by the disease.
Regulation 141 governs the process of designating a drug as an orphan drug.
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?)
Firstly, an orphan drug must be designated as such before applying for a marketing authorization. The process of designation of an orphan drug follows Article 5 et seq. of the Regulation 141.
An application to the European Medicines Agency (the “Agency”) for a medicinal product to gain orphan drug status may be submitted at any stage of the development of the medicinal product. The Committee for Orphan Medicinal Products (the “Committee”), established within the Agency, then gives its opinion on the medicinal product within 90 days of a (duly) submitted application. The European Commission then decides whether the medicinal product can be designated as an orphan drug within 30 days of the issued opinion. Once approved by the European Commission, the orphan drug is entered in the Community Register of Orphan Medicinal Products.
The process for designation is based on the (rare) disease status (see above); there is no differentiation between sponsors from third-countries and the EU.
Once successfully designated, the sponsor can apply for registration in accordance with the relevant EU regulation on authorization of medicinal products (“MPA Regulation”)1, i.e. through the general registration process used for any other medicinal product. Once successfully registered, the orphan drug may be used throughout EU member states.
The registration is valid for five years and may be extended for an indefinite term after further review. However, the European Commission can also decide to extend the registration for an additional five-year period (thus postponing the possibility of an indefinite extension by five years), for reasons of pharmacovigilance. As “exposure of an insufficient number of patients to the medicinal product concerned” can be explicitly stated as grounds for justifying an additional five-year registration, this exception may apply to orphan drugs in particular.
4. Does your country have pro- visions for relaxed clinical trial/ scientific evidence requirements in respect of Orphan Drugs as compared to other drugs?
A distinction between the designation and authorization of an orphan drug must be made.
The requirements for the designation of orphan drugs are contained in the directly applicable Regulation 141, and are specific to orphan drugs. Additionally, given that an application for designation of such medicinal product can be made at any stage of the product’s development, the documentation required can be considered relaxed. That said, it must be noted that, upon approval of the designation, the sponsor is obliged to submit to the Agency an annual report on the state of development of the designated orphan drug, including, e.g., a review of ongoing clinical studies.
Marketing authorization of an orphan drug follows the rules for a centralized procedure under the MPA Regulation. This procedure does not offer any relaxed approach; however, there are alternative marketing authorizations which allow for some leeway in supporting documentation and scientific evidence requirements. Specifically, there are (i) a conditional marketing authorization and (ii) a marketing authorization under exceptional circumstances, as described below.
5. Is there an expedited pathway for Orphan Drugs?
Conditional marketing authorization
The MPA Regulation along with the Commission regulation on conditional marketing authorization (“Commission MA Regulation”)2 provide for an expedited pathway for a range of medical products, including orphan drugs.
In duly justified cases, in order to meet “unmet medical needs of patients” a marketing authorization may be granted on the basis of temporarily less complete data than what would be required under the “standard” procedure, provided that the risk-benefit balance for granting such marketing authorization is positive, as well as provided that other requirements arising from the regulation are met. The term “unmet medical needs of patients”, as defined in the MPA Regulation, means a condition for which no satisfactory method of diagnosis, prevention or treatment authorized in the EU exists or, even if a method exists, the medicinal product concerned represents a major therapeutic advantage to those affected.
Additional specific obligations (including a timeframe for their completion) may be imposed in a conditional marketing authorization, such as the obligation to conduct additional studies concerning the risk-benefit balance, etc. Information on such specific obligations is then made available to the public, and the fact that the medicinal product has been granted a marketing authorization subject to specific obligations must be included in the summary of the product characteristics and the package leaflet. Failure to fulfil the specific obligations will result in a change, suspension or revocation of the marketing authorization.
Due to their conditional nature, conditional marketing authorizations are valid for one year only, though on a renewable basis. A renewal application must be submitted six months prior to the expiry of the marketing authorization. Additionally, any conditional marketing authorization can be transformed into a “standard” marketing authorization under the MPA Regulation, provided its outlined specific obligations have been met.
Accelerated assessment procedure
It should also be noted that under the MPA Regulation an applicant may request a medicinal product to be assessed in an accelerated assessment procedure. However, this procedure is only possible if the medicinal product in question is of major interest from a public health point of view, in particular, from the point of view of therapeutic innovation.
Finally, “a marketing authorization under exceptional circumstances” may be issued, especially in relation to orphan drugs (please note that orphan drug designation alone is not sufficient to successfully request a marketing authorization under exceptional circumstances).
Under relevant provisions of the Commission MA Regulation, an applicant can file for such marketing authorization provided that the applicant can demonstrate that it is not possible to provide comprehensive data on the efficacy and safety under normal conditions of use, because (i) the indications which the product in question is intended for are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or (ii) in the present state of scientific knowledge, comprehensive information cannot be provided, or (iii) it would be contrary to generally accepted principles of medical ethics to collect such information. Additional obligations may be imposed.
A marketing authorization under exceptional circumstances is valid for five years and may be extended for an indefinite term after further review (or for an additional term of five years based on a decision by the European Commission, as described above), similarly to a general marketing authorization.
6. Are foreign marketing authorizations recognized in your jurisdiction for Orphan Drugs? If yes, marketing authorizations from which countries are recognized?
Where the EU is concerned, once granted by the European Commission, a centralized marketing authorization is valid in all member states as well as throughout the European Economic Area (i.e. Iceland, Liechtenstein and Norway). This also means that should the medicinal product fail to receive an authorization, it may not be placed on the market anywhere in the EU. All decisions of the European Commission are published in the Union Register of medicinal products. However, it has to be noted that this does not apply to reimbursement, which is awarded on an individual country-by-country basis.
7. Can Orphan Drugs be reimbursed? If so, is there a specific reimbursement procedure for Orphan Drugs?
Under Czech law the reimbursement of orphan drugs is possible; however, there is no specific reimbursement procedure for orphan drugs, i.e. general reimbursement provisions apply.
Even though there is no specific provision or regulation pertaining to orphan drugs, certain provisions of Act No. 48/1997 Coll., on Public Health Insurance (“PHI Act”) are often used to reimburse such medicinal products. These provisions relate to “highly innovative products”, which the PHI Act defines as medicinal products containing an active substance that (i) can be used for the treatment of a disease that so far could not have been treated by any other medicinal product or substance, or that (ii) presents a major improvement in treatment.
There is no need to show cost effectiveness or treatment results in clinical practice for an orphan drug to be reimbursed as a highly innovative product, but certain other requirements apply, including the following: (i) the reimbursement must be in the public interest (a fact assessed by the State Institute for Drug Control (“SÚKL”), i.e. the relevant Czech public authority), (ii) the available information must sufficiently evidence that the orphan drug under consideration is beneficial in a particular treatment, and (iii) the orphan drug must already be reimbursed in at least two countries of a reference basket.
If approved, the highly innovative product is granted reimbursable status for 24 months only; this can be extended for an additional 12 months, i.e. the product may be reimbursed as a highly innovative product for a maximum of 36 months.
Additionally, it must be noted that the PHI Act contains a specific provision – Section 16. This provision allows for the reimbursement of any medicinal product for a patient on an individual case-by-case basis, provided that the medicinal product is the only possible treatment given the health condition of the specific patient. Note that this provision is interpreted very restrictively.
8. How are the prices of Orphan Drugs regulated?
No specific regulation applies to the establishment of orphan drug prices, i.e. the general rules for all medicinal products apply. The relevant public authority, the SÚKL, regulates prices by establishing a maximum price.
The most common way to establish a maximum price is by calculating the average of the three lowest prices from countries included in the reference basket.
If this method is not feasible (e.g. the medicinal product in question is not available on the markets in at least three countries included in the reference basket), other methods can be used, such as establishing the price based on the price of a comparable medicinal product, etc.
9. In case of reference price based on a basket of countries, what countries are included?
All EU countries are included with the exception of: Bulgaria, Czech Republic, Estonia, Luxembourg, Germany, Austria, Romania, Greece, Cyprus and Malta.
10. Have there been any significant legal/judicial developments in relation to Orphan Drugs in your country?
An amendment to the PHI Act and related legislation is currently (May 2021) in the early stages of the legislative procedure, in the Chamber of Deputies of the Parliament of the Czech Republic, which intends to introduce an orphan drugs-specific regulation on reimbursement, among other things.
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 above-mentioned amendment to the PHI Act and related legislation is still in the very early stages of the legislative procedure; thus, it is currently impossible to estimate the likely date of its entry into force.
(1) Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Union procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
(2) Commission Regulation (EC) No 507/2006 of 29 March 2006 on the conditional marketing authorization for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004 of the European Parliament and of the Council